Method for treating a patient having a pelvic floor dysfunction

ABSTRACT

A method to treat a patient having a pelvic floor dysfunction or overactive bladder disorder by establishing a neurostimulator having a processor and an electrical signal generator to generate a stimulation signal. The processor is set to one or more parameters effective in the treating of the patient&#39;s pelvic disorder or dysfunction including overactive bladder disorder when the stimulation signal is applied to a saphenous nerve of the patient. The neurostimulator is configured to provide the stimulation signal to a stimulator in accordance with a stimulation protocol. At least one stimulator is positioned next to a portion of the saphenous nerve of at least one lower limb of a patient. The processor is operationally activated to provide the stimulation signal to the stimulator for treatment of the patient.

REFERENCE TO RELATED APPLICATIONS

This Patent Application is a Continuation Application of patentapplication Ser. No. 15/439,415 filed on 22 Feb. 2017, currentlypending, which was filed as a Continuation of application Ser. No.15/160,468 filed on 20 May 2016 (issued as U.S. Pat. No. 9,610,442),which is based upon U.S. Provisional Patent Application Ser. No.62/171,549 filed 5 Jun. 2015 and U.S. Provisional Application Ser. No.62/165,037 filed 21 May 2015.

This Patent Application is additionally a Continuation-In-Part ofapplication Ser. No. 14/553,427 filed on 28 May 2016 which is based uponProvisional Patent Application Ser. No. 61/909,679, filed on 27 Nov.2013, Provisional Application Ser. No. 61/944,744, filed on 26 Feb.2014, and, Provisional Patent Application Ser. No. 62/024,912, filed on15 Jul. 2014.

INCORPORATION BY REFERENCE

This patent application hereby incorporates by reference, U.S. patentapplication Ser. No. 14/553,427, U.S. patent applications Ser. Nos.15/160,468, 61/909,679, 61/944,744, 62/024,912, 62/165,037, and62/171,549 which are hereby incorporated by reference in theirentireties for all purposes.

FIELD

The subject concept relates to the field of modulating biologicaltissue.

BACKGROUND

Nerve stimulation (neurostimulation) technology includes applicationssuch as electrical neuromodulation, functional electrical stimulation,and therapeutic electrical stimulation. Nerve stimulation is aneffective clinical tool used to treat various chronic medical disordersand conditions. Examples include (1) deep brain stimulation (DBS) fortreating Parkinson's disease and essential tremor, (2) spinal cordstimulation for treating pain and urinary dysfunction, and (3)peripheral nerve stimulation for treating overactive bladder, pelvicfloor disorders and dysfunctions, pain, obstructive sleep apnea,headache, migraine, epilepsy, depression, hypertension, cardiacdisorders, and stroke. Peripheral nerves may include, for example, thevagus nerve, occipital nerve, cranial nerves, spinal nerves, pudendalnerves, cutaneous nerves, and the sciatic and femoral nerves.

Therapeutic efficacy of neurostimulation technology is attributed toselective activation of targeted tissue or neural circuitry, using astimulation signal that is appropriate for a selected target. This isnormally achieved by low recruitment of non-targeted tissue or neuralcircuit(s). Unintended activation of non-targeted nervous tissue, by abroad or incorrectly localized stimulation field, may deter therapeuticbenefit. Unintended modulation of biological system(s) may also be dueto, for example, inhibitory rather than, or in addition to, excitatoryeffects, or other unwanted activity or physiological responses.Unintended modulation may produce side-effects and outcomes that arecontrary to the intended response.

The state-of-the-art method, for addressing the issue of selective nerveactivation, is to minimize the distance between a stimulating electrodeand the nerve targets, and in certain cases isolate the electrode withinsulating material. This usually requires precise implantation of anelectrode, connecting wires, and a pulse generator (e.g., for brain orspinal cord stimulation). This solution may involve highly-invasivesurgery that may be associated with significant risk and discomfort.Disadvantages may include neural or vascular damage, revision surgeries,periodic replacement of pulse generator, surgical complications, andpotentially life-threatening infections.

The peripheral nervous system provides a neural substrate that isrelatively conducive for selective nerve stimulation of individual nervebranches. However, long-term viability of permanently implantedneurostimulation systems can become complicated by issues related torepeated mechanical movement of lead wires connected to the pulsegenerator (e.g., lead fracture and/or component migration). Althoughtranscutaneous electrical stimulation can provide a more simple andnon-invasive approach, selective nerve activation is not readilyachieved.

In many instances, the ability to selectively activate a specific neuraltarget by implanted nerve stimulation systems is also far from idealwhen systems with multiple components must be implanted. Thecurrent-state-of-the-art methods aimed at improving stimulationselectivity involve the design and implementation of various types ofneural interfaces: multi-polar (or multi-contact) deep brain stimulationDBS leads, multi-polar paddle-type electrodes for spinal cord orsubcutaneous stimulation, microelectrode arrays (e.g., Utah Array orMichigan Probe, or Huntington Medical Research Institute electrodes),and multi-contact nerve cuff electrodes (e.g., Cyberonics Inc., CaseWestern Reserve University). A main objective of these electrode designsis to maximize the number of electrode contacts such that an‘optimally-positioned’ stimulation location, or an ‘optimal combinationof one or more electrode contacts’, can be used to achieve effectivetherapeutic outcomes. Improved nerve stimulation selectivity canincrease the efficacy of treatment in some instances, such as unintendedstimulation of adjacent nerves.

Advances in minimally-invasive nerve stimulation have been realizedclinically. Wireless implantable electrode probes have been developedfor achieving less invasive methods of selective nerve stimulation. TheBION (Alfred Mann Foundation, Boston Scientific) is a glass or ceramiccovered electrode that can be percutaneously injected into a region ofinterest. It can be self-powered or passively charged by radio frequency(RF) pulses. Long-term use may be complicated by migration of the BIONfrom its original implant location. This migration may cause bothreduced therapeutic effects and increased stimulation-evoked sideeffects due to activation of other (non-target) tissue. Nervestimulation systems (e.g., MicroTransponder Inc. SAINT™ System) whichare smaller, less expensive, and less technically complicated than theBION may be advantageous in treatment of some disorders. Micron Deviceshas developed an implantable neurostimulators, similar to the BION,which uses wireless power in the RF and/or microwave frequency rage andnon-inductive antennas which receive electromagnetic energy radiatedfrom a source located outside of the patient's body to produce nervestimulation. Energous technology is developing wireless technology thatutilizes multiple antennae to provide improved transmission andharvesting of wireless energy and is developing within the implantabledevice space. These technologies may allow smaller form factors.

Another example of nerve stimulation technology is the floatinglight-activated micro-electrode (FLAME). FLAME uses an analogous designapproach to the BION however, instead of RF pulses, the implantedelectrode converts near infrared light into electrical pulses. Clinicaluse of FLAME technology is currently limited, primarily due to poorpenetration of light into biological tissue and other technical hurdles.

Transcutaneous magnetic stimulators (TMS), termed “transcranial magneticstimulators” when used for brain stimulation, are used to treatdisorders such as migraine (e.g. Neuralieve Inc.) by using an externalmagnetic stimulation device to stimulate central or peripheral tissuetargets. The fields induced inside the tissue by one or more pulses(pulsed electromagnetic stimulation) may be less localized than desired.

Transcutaneous electrical nerve stimulation (TENS) is anothernon-invasive approach to activating nervous tissue. Companies such asCefaly have designed TENS systems to work specifically on nerve cellsaffected by pain. The TENS system developed by Cefaly works byintroducing electric impulses to act on the nerves that transmitmigraine pain such as a bifurcation of nerves known as the trigeminalnerve. In addition to pain, TENS systems have been used to applyelectrical fields to the brain in order to modulate sleep, anxiety,depression, pain, attention, memory, and other types ofcognitive/sensory processing. Tens systems are also being developed toenhance performance of athletes. The current system and method may beused with such a TENS system in order to focus on an area, orpopulation, of nerves that are electrically activated.

Electrocore Inc. has developed both non-invasive electrical (e.g., TENS)and implantable magnetically driven stimulators that electricallystimulate nerves such as the vagus nerve. For vagus nerve stimulation(VNS) therapy, a hand-held device is placed on the surface of the skinjust above the vagus nerve, which is palpated by the pulsating carotidartery. The clinical efficacy of this approach is currently undergoingvalidation. Given the anatomical characteristics of the vagus nerve(e.g., distance from the skin surface, embedded within a neurovascularbundle), there may be challenges associated with TENS based VNS. Factorssuch as overweight patients with subcutaneous tissue (e.g., fatdeposits) may prove challenging since this increases the distancebetween the stimulating electrode and the vagal target.

Uroplasty has developed both cutaneous and percutaneous stimulationsystems for the treatment of urological disorders. The main therapycurrently implemented involves posterior tibial nerve stimulation, whichrelies on percutaneous injection of a needle electrode near thepatient's ankle.

Both Electrocore Inc and Uroplasty are currently engaged in developingimplantable stimulation systems for activating nervous tissue, where theimplanted stimulator is wirelessly powered by magnetic induction. Thisapproach obviates the need for using an implantable battery,percutaneous or sub-cutaneous leads connecting to a power source, and itmay also decrease the complexity of the implanted circuitry. This systemhas not yet completed clinically trials, and so the associateddisadvantages are currently unknown.

Modulation of biological tissue, such as nervous tissue, presents theopportunity to treat a myriad of biological and physiological conditionsand disorders. Modulation can include interacting with, and controlling,a patient's natural processes. Modulation of tissue can include nervemodulation such as inhibition (e.g. blockage), activation, modification,up-regulation, down-regulation, or other type of therapeutic alterationof activity. The resulting biological response may be electrical and/orchemical in nature and may occur within the central or peripheralnervous systems, or the autonomic or somatic nervous systems. Bymodulating the activity of the nervous system, for example, throughactivation or blocking of nerves, many functional outcomes may beachieved. Motor neurons may be stimulated to cause muscle contractions.Sensory neurons may be blocked, to relieve pain, or stimulated, toprovide a biofeedback signal to a subject. In other examples, modulationof the autonomic nervous system may be used to adjust variousinvoluntary physiological parameters, such as heart rate and bloodpressure.

SUMMARY

A transcutaneous tissue stimulation system and method is provided whichincludes an electrical generator positioned external to a patient. Astimulator is electrically coupled to the electrical generator and ispositioned on the surface of the patient's skin. An implanted,electrically conductive member is positioned on, or contiguous to, atarget nerve tissue for stimulation of the target nerve tissue to modifythe electrical field signals generated by the electrical generator andprovided by the stimulator for the purpose of modulating signals fromthe nerve tissue to the brain, to the central or peripheral nervoussystem, or other target, of the patient.

Stimulation systems and methods are described for providing advantagesrelated to increasing therapeutic efficacy of nerve stimulation,improving the comfort of a patient relative to other therapeuticsolutions, decreasing the cost of treatment, and/or providing for asimple treatment and/or implantation procedure.

An objective of the current system is to provide systems and methodswhich provide selective nerve stimulation, and stimulate specific nervebranches or selected portions of a nerve or nerve fascicle.

Another objective of the current system is to provide one or more smallimplanted components to provide selective nerve stimulation and therebyoffer improved long-term clinical therapy. This system and method aimsto avoid activation of non-targeted nervous tissue, which can both limitthe overall therapeutic effects and exacerbate stimulation-evoked sideeffects.

Another objective of the current system and method is to provide for anerve stimulation system having external components and an implantedpassive element which is configured to allow therapy to achieve thesame, or improved therapeutic benefit as that which would otherwise beachieved when using only transcutaneous nerve stimulation without animplanted passive element.

Another objective is to provide systems and methods for providingstimulation of tissue using complementary or “paired” configurations ofexternal stimulation elements and subcutaneously implanted passiveelements.

Another objective is to provide systems and methods for providing aselective increase in neural excitability, where a single neural target(located among one or more other nerves) is independently activated ormultiple nerves are activated independently using one or more implantedelements and applying different stimulation parameters such asstimulator location, electrode contacts which are active, amplitude,frequency, duty cycle, and waveform.

Another objective is to provide systems and methods for achievingeffective therapeutic nerve activation with relatively lower stimulationamplitude and/or shorter pulse width than what is achievable using priorart methods (e.g., TENS).

Another objective is to provide systems and methods for reducedactivation of non-targeted nervous tissue (i.e., minimize stimulationspillover).

Another objective is to provide systems & methods for decreasing nervestimulation-evoked side effects.

Another objective is to provide systems and methods for providingimproved transcutaneous electrical nerve stimulation, intra-vascularstimulation of nervous tissue, and augmented selective activation ofperipheral and central nervous system tissue.

Another objective is to provide systems and methods for providingimproved TENS for certain fibers during VNS (e.g., small myelinatedB-fibers and/or unmyelinated C-fibers), while avoiding, for example,A-Type fibers.

Another objective is to provide systems and methods for providingimproved modulation of tissue targets that may include glandular tissue,fatty or lipid tissue, bone tissue, muscle tissue, and nerve tissue.

Another objective is to provide systems and methods for improving anumber of clinical conditions and their related treatments including,for example: a) Overactive Bladder treatment (or any disorder orcondition related to bladder activity or voiding) by posterior tibialnerve or sacral nerve stimulation; b) Chronic pain and treatment bystimulation of the lower back or lower extremities; c) treatment relatedto migraine and headache; d) Obstructive sleep apnea and treatmentrelated to hypoglossal, vagal, or superior larygeal nerve stimulation;e) various conditions such as epilepsy, headache, and depression whichmay be treated by vagus nerve stimulation; and f) various otherconditions that may be treated by improving selective targeting ofspecific tissue.

Another objective is to provide systems and methods for providingstimulation of tissue using improved configurations, materials,orientations, embodiments, and spacing of external stimulation elements,cutaneous stimulation elements, and implanted passive elements which arenot physically connected to the stimulation sources.

Another objective is to provide systems and methods for providingstimulation of a first tissue target that is approximately cutaneous andalso providing for stimulation of a second target that is a nerve thatis relatively distal from the skin surface.

Another objective is to provide systems and methods for augmenting othertherapies in order to increase the number of patients that benefit,augment the magnitude of therapeutic benefits, and/or decrease thefrequency of repeated therapeutic interventions that may besignificantly more invasive.

Another object of the subject system and method is to allowmagnetically-induced electric fields, or sound or light stimulation, toachieve more specific modulation of target tissue or neural circuits.

Another object of the system and method is to permit a functionalfocusing and/or shaping of a TMS field so that selective activation ispromoted.

Another object of the invention is to selectively stimulate nervetargets using stimulation signals that are specific to those targets(e.g. having a target specific frequency that is selected based uponassessment of the patient), and adjusting or switching the nerve targetsor the stimulation signals to become or remain effective, and wellselected, based upon the understanding that the full posterior tibialnerve and its branches, as well as other nerves disclosed herein mayprovide unique acute and prolonged post-stimulation responses related tobladder activity and related treatments.

A further object of the invention is to selectively stimulate nervetargets, including nerve branches or combinations thereof, usingstimulation signals that are effective and specific to those targets forthe treatment of a pelvic floor disorder.

A further object of the invention is to selectively stimulate novelnerve targets in novel manners including the saphenous nerve, andassociated L2, L3, and L4 spinal nerve roots and moreover improvingtherapy by, for example, using stimulation signals that are defined forthose targets and which have been shown to provide therapy of a patient,either alone or in combination with other currently known targets, forthe treatment of a pelvic floor disorder, and in order to modulate,increase, or decrease bladder activity and also to provide symptomrelief.

These and other objectives and advantages of the invention will now bedisclosed in the figures, detailed description, and claims of theinvention.

In the illustrated embodiments, any steps shown in the figures may occurin a different order, may be repeated, may lead to different steps ofthe method shown within each figure, or may lead to steps shown in otherfigures. Steps and components shown may be included or excluded from aparticular embodiment, and this may occur conditionally, or according tothe system or treatment protocol implemented by a therapy program. Thetherapy program may be implemented partially or fully by one or moreprocessors of a medical system which may include an external, or apartially or fully implantable neurostimulator. The therapy program canbe adjusted according to control by, or therapy plan implemented by, apatient, doctor, remote medical service, or caregiver.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1a-1b show a schematic diagram of one embodiment of an enhancedtranscutaneous nerve stimulation (eTNS) system implemented in a lowerlimb, where the system, or finite element model thereof, includes asurface electrode, and a passive element (implantable passive componentor “IPC”) that is placed in close proximity to the posterior tibialnerve, and FIG. 1b is a close-up of the area enclosed by the dashed boxof FIG. 1 a.

FIG. 1c shows a schematic diagram representing another embodiment of theenhanced nerve stimulation system, or finite element model thereof, andincludes a pair of stimulating surface electrodes, with lengths (L1,L2)and widths (W1,W2), placed on the surface of the skin of a patient, withan inter-electrode distance (D1), as well as an implant (IPC) located ata given depth distance (D2) from the skin surface.

FIG. 2a is a graph showing results from a computer simulation thatdepicts the relationship between the activating function (AF: measure ofneural excitability) and the distance between the IPC and the targetnerve, where the distance between the surface electrode and the nerve iskept constant (a higher AF indicates a lower nerve activationthreshold).

FIG. 2b is a graph showing computer simulation results that depict theeffects of the IPC on the AF, and the distance between the surfaceelectrode and the target nerve was increased (depth from skin surface=7mm to 30 mm).

FIG. 3a is a graph showing modeled results of relative “neuralexcitability” as a function of nerve depth from the skin surface (therelative excitability was calculated as the ratio of the AF between the“IPC present” condition and an “IPC absent” condition).

FIG. 3b is a graph showing modeled results of the effects of theelectrical conductivity of the IPC on the relative neural excitability(AF).

FIG. 4a is a graphical representation showing data from computersimulations (according to setup shown in FIG. 1c ) that calculated theAF generated by conventional TENS (no IPC) as a function of both thedepth of the nerve (D2, depth distance to nerve from cutaneousstimulation electrode) and the distance between the anode and cathodesurface electrodes (D1, inter-electrode distance is the x-axis).

FIG. 4b is a graphical representation showing data from computersimulations that depict the effects of IPC thickness (i.e., thickness ofcylindrical wall of nerve cuff) on enhancing neural excitability (“MaxAF”) and shows that, compared to the case of ‘no IPC’, an IPC thicknessof less than 0.3 mm increases AF, while a thickness above 0.3 mm wasfound to reduce neural excitability.

FIG. 4c is a graphical representation showing data from computersimulations showing the normalized Max AF as a function of both thethickness of the nerve cuff (IPC) and the depth distance of the nervefrom skin surface (ND).

FIG. 5a is a graph of data from computer simulations, (finite elementmodel of FIG. 1a scaled to dimensions of a rat), that depict therelationship between the length of the IPC (cuff-type) and the distancebetween the bipolar stimulating surface electrodes (similar to the setupshown in FIG. 1c ).

FIG. 5b is a graph of data from computer simulations (finite elementmodel of FIG. 1a scaled to dimensions of a human) of enhancedtranscutaneous nerve stimulation (eTENS) that are in agreement withfindings from an experimental rat model (i.e., results of FIG. 5a ).

FIG. 6a is a graph of data from a computer model of eTENS (scaled todimensions of a rat) involving monopolar surface stimulation in whichthe surface electrode (area=1 mm×1 mm) and IPC (nerve cuff length, NCL=1mm) are of similar dimensions, and initially aligned as depicted in theinset diagram (misalignment=0 mm) and in which the relative excitability(% AF normalized to TENS with no IPC) is calculated as the IPC isshifted along the nerve (surface electrode is stationary) such that themisalignment increases from 0 mm to 6.5 mm.

FIG. 6b is a graph of data from a computer model of eTENS (scaled todimensions of a rat) involving monopolar surface stimulation, in whichthe dimensions of the surface electrode (area=1 mm×1 mm) are smallerthan the IPC (nerve cuff length, NCL=5 mm), and in which the IPC isshifted along the nerve (surface electrode is stationary), such that themisalignment increases from 0 mm to 6.5 mm

FIG. 7 is a graph of data relating to the effects of the electricalconductivity of the IPC (monopolar stimulation model in FIG. 6a ) on the“relative neural excitability (%)”, as the conductivity values wereincreased from 9.43e−14 to 9.43e+11.

FIG. 8 is a graph of data from a computer model of eTENS (monopolarstimulation model in FIG. 6a ), where the effects of IPC length onrelative excitability were simulated for an IPC with 0.02 mm nerve cuffthickness (NCT, refer to FIG. 4b ), and where the length of the IPC(‘cuffed around the nerve’) was increased from 0 mm (no-IPC baselinecondition) to 10 mm for 4 different cases of nerve depth (ND) from theskin surface.

FIG. 9a is a graph of data from an experiment conducted in ananesthetized rat, where a surface electrode (5 mm×5 mm) was placed onthe posterior-medial surface of the hind limb to stimulate the posteriortibial nerve and a pair of insulated stainless steel wires was insertedinto the ipsilateral foot to measure muscle activation (EMG). The return“anodic” electrode was a needle inserted percutaneously through theabdominal fat pad, ipsilateral to the stimulated leg.

FIG. 9b shows the experimental set-up of a computer simulation, where asurface electrode (10 mm×10 mm) was positioned over an array ofperipheral nerves (diameter=1 mm, length=100 mm) and the target nerve(a1) was positioned directly below the stimulating electrode at a depthof 3 mm from the skin surface. Additional nerves were positioned in bothvertical (a2 to a5) and lateral (a12 to a15) fashion with respect to a1.The distance between each nerve was 10 mm.

FIG. 9c is a graph of data derived from the computer simulation of FIG.9b , where the target nerve (a1) shows increased AF which peaks when theIPC length is between 10 and 40 mm, while the non-target nerves showreduced AF, supporting both increased sensitivity and specificity,respectively, to the stimulation electrode.

FIG. 10a is a schematic system view containing relevant neuroanatomicallandmarks for electrical neuromodulation of the urinary bladder, withthe urinary bladder and urethra innervated by the pelvic and pudendalnerves, respectively.

FIG. 10b schematically depicts the posterior tibial nerve (PTN) andsaphenous nerve descending the posterior-medial aspect of the human leg.The PTN divides into the medial plantar nerve (MPN) branch, lateralplantar nerve (LPN) branch, and calcaneal nerves; whereas the saphenousnerve innervates the skin and underlying tissue layers along themedial-posterior surface of the lower leg/ankle/foot area. Suitablecandidate implant locations for nerve cuffs (which can serve as the IPCof the current invention or which may operate as electrodes inconjunction with an implanted neurostimulator) are shown proximate toindividual nerves.

FIG. 11 schematically depicts the selected spinal nerve roots thatconverge to form the pudendal (S2-S4) and posterior tibial (L4-S3)nerves. Two surgically placed objects (e.g., nerve cuffs) are indicatedas IPCs (10 f and 10 g) on the S3 and L4 roots, respectively.

FIG. 12 is a set of graphs of experimental data that characterizes theeffects of PTN stimulation on the bladder of urethane-anesthetized rats.At 5 Hz PTN stimulation (top trace) both acute inhibition duringstimulation (black bar) and prolonged inhibition following stimulation(gray bar labeled as POST-STIM) were found. At 50 Hz PTN stimulation(bottom trace), only post-stimulation excitation (gray bar labeled asPOST-STIM), was found.

FIGS. 13 a, b, c are graphs showing summary data of electricalstimulation of (A) PTN, (B) medial plantar nerve (MPN), and (C) lateralplantar nerve (LPN) in anesthetized rats (e.g. summaries of raw datasuch as that seen in FIG. 12). Bladder inhibition (defined by %reduction in bladder contraction rate (BRC) with respect to baseline) isobserved during stimulation at lower frequencies (e.g., 5 Hz to 20 Hz),whereas bladder excitation is observed at 50 Hz for PTN and LPNstimulation.

FIGS. 14 a, b, c are graphs of summary data of percentage of experiments(total 11 rats) that exhibited an acute reduction in BRC (i.e. acutebladder inhibition) during each 10-minute stimulation trial of the PTN,MPN, and LPN in anesthetized rats.

FIGS. 14 d, e, f are graphs of summary data of percentage of experiments(total 11 rats) that exhibited a prolonged reduction in BRC (i.e.prolonged bladder inhibition) following each 10-minute stimulation trialof the PTN, MPN, and LPN in anesthetized rats.

FIG. 15 is a graph of experimental data from an anesthetized rat, whereelectrical stimulation (0.3 mA, 5 Hz) of the Saphenous nerve (branch wasaccessed below the knee) resulted in an acute 25% decrease in BCR duringstimulation as evidenced by the top trace, while middle trade showsother recorded activity and the lower trace shows the duration of thepulse train.

FIG. 16 shows alternative exemplary embodiments of different electricalnerve stimulation patterns that can be used with the present inventionto improve various neuromodulation therapies.

FIG. 17 is a logic flow block diagram showing a method for providingtreatment to a patient.

FIG. 18a is a schematic diagram of a tissue stimulation system which maybe used to realize the current invention including the provision oftissue stimulation.

FIG. 18b is a schematic diagram of a tissue stimulation system includingan implantable electrical stimulation system which may be used torealize the current invention.

FIG. 19 is a schematic diagram of an alternative nerve stimulationsystem which may be used with transcutaneous stimulation.

FIG. 20a is a schematic diagram of an embodiment of a system forselective (eTENS-based) activation of multiple nerves using a bipolarstimulation paradigm.

FIG. 20b is a schematic diagram of an embodiment of a system forselective (eTENS-based) activation of multiple nerves using a monopolarstimulation paradigm.

FIG. 21 is a schematic diagram of the enhanced transcutaneous nervestimulation (eTNS) system for electrically activating nervous tissue atsites in the neck and upper chest.

FIG. 22a is a logic block flow diagram for a method of using the eTNSsystem to stimulate using more than one IPC.

FIG. 22b is a logic block flow diagram for a method of using the eTNSsystem as a medical screening test.

FIG. 22c is a logic block flow diagram for a method of providing a firststimulation treatment and second stimulation treatment for providingtherapy.

FIG. 23a is a schematic diagram of an embodiment of the subject systemin which a plurality of IPCs provides for the shaping of an electricalfield.

FIG. 23b is a schematic diagram of an alternative embodiment of thesubject system in which a plurality of IPCs provides for the shaping ofan electrical field.

FIG. 24a is a schematic diagram of an embodiment of a controller for aportable TNS system.

FIG. 24b is a perspective schematic view of a portable TNS system.

FIG. 24c is a perspective schematic view of a stimulator for providingtissue stimulation using at least one stimulator.

FIG. 24d is a perspective schematic view of a stimulator for providingtissue stimulation using two stimulators.

FIG. 25 is a schematic view of a multi-contact array stimulator.

FIG. 26a is a schematic view of an embodiment of a multi-contactstimulator array and a multi-contact IPC array.

FIG. 26b is a schematic view of an embodiment of an IPC, in which theconductive material is limited to a single conductive strip.

FIG. 26c is a schematic view of an embodiment of an IPC, where aninsulating material is applied to the external surface of the conductingmaterial.

FIG. 27 is a schematic view of a further embodiment of a portable TNSsystem and stimulation templates.

FIGS. 28a-e show schematic views of further embodiments of IPCs.

FIGS. 29a,b show schematic views of still further embodiments of IPCs.

FIGS. 30a-d show schematic views of additional embodiments of IPCs.

FIG. 31 is a schematic view of an embodiment of an IPC, which is used toachieve enhanced nerve activation by trans-vascular electricalstimulation.

FIG. 32 is a schematic view of two arrays of surface stimulators and anIPC.

FIG. 33 is a schematic view of an embodiment of an implantable activecomponent.

FIG. 34 shows graphs of experimental data for changes in bladderpressure evoked by saphenous nerve (SAFN) stimulation in an anesthetizedrat. Compared to baseline, both acute and prolonged bladder inhibitionare achieved by stimulation at 25 μA and 20 Hz.

FIG. 35 shows experimental data of acute bladder inhibition (during SAFNat 25 μA and 10 Hz), followed immediately by bladder excitation duringthe prolonged response phase (10 minutes after stimulus pulse train).

FIGS. 36a and 36b show summaries of the percentage of experiments thatresulted in inhibitory, neutral, or excitatory bladder responses (acuteand prolonged), across stimulation frequencies between 2 Hz and 50 Hz,applied at 25 μA

FIG. 37 shows a summary of percentage change in bladder contractionrates (BCR) for all SAFN stimulation (25 μA) trials that were identifiedas inhibitory (>10% decrease in BCR).

FIG. 38 shows a summary of mean percentage change in BCR for all SAFNstimulation (25 μA) trials that were identified as excitatory (>10%increase in BCR).

FIG. 39 shows experimental data for both acute and prolonged bladderinhibition evoked by SAFN stimulation applied at 50 μA and 10 Hz, withpre-stimulation bladder activity circled in the middle panel.

FIG. 40 shows summary data for the percentage of experiments thatresulted in inhibitory, neutral, or excitatory bladder responses, acrossstimulation amplitudes of 25 μA, 50 μA and 100 μA all applied at 10 Hz.

FIG. 41 is a summary of percentage changes in BCR for all SAFNstimulation trials at 10 Hz that were identified as inhibitory (toppanel) and excitatory (bottom panel).

FIG. 42 is a schematic view of small “microneurostimulator” devices andnerve cuff embodiments configured for stimulating target nerves.

FIG. 43 is a schematic view of an alternative embodiment of a nervecuff, where the electrode contacts are located to provide selectivestimulation of nerve targets.

FIG. 44 is a schematic view of embodiments of an electrode array havingcanals for physically separating, and selectively stimulating, nervefascicle targets.

FIG. 45 is a schematic view of an alternative embodiment of a nervestimulation system.

FIG. 46 is a schematic view of an alternative embodiment of a nervestimulation system.

FIG. 47 is a schematic drawing of a peripheral electrode which is anerve cuff designed to selectively activate one or more branches of acompound nerve trunk such as the posterior tibial nerve.

FIG. 48 is a schematic view of further embodiments of an electrode whichis a nerve cuff.

FIG. 49 is a schematic view of further embodiments of a nerve cuff.

FIG. 50a is a diagram of a multi-contact planar and lead-type electrodearray for selectively activating one or more nerve branches such asbranches of the saphenous nerve and posterior tibial nerve.

FIGS. 50b-d are schematic diagrams of an implantable neurostimulator anda stimulation system which uses an electrode array grid accessory.

FIG. 50e is a schematic diagram of various types of neurostimulators,stimulators, and stimulation locations near and in a foot.

FIG. 51 is a schematic drawing of multi-contact array electrodes thatare implanted to selectively activate one or more targets of the lumbarspinal cord and/or lumbar spinal nerve roots.

FIG. 52 shows the steps in a method of providing nerve stimulation.

FIGS. 53a,b show neurostimulator systems having at least oneneurostimulator that may be implanted in a location to providestimulation to multiple spinal or lower limb targets.

FIG. 54 shows alternative embodiments of neurostimulation systemsimplemented on the medial side of a leg.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Reference will now be made in detail to exemplary embodiments of thepresent disclosure, examples of which are illustrated in theaccompanying drawings. Wherever possible, the same reference numberswill be used throughout the drawings to refer to the same or likecomponents. When titles are provided to the different sections of thedisclosure these are merely to highlight certain themes in theapplication and are not meant to constrain or limit the inventionconcept in any manner.

Embodiments of the present disclosure relate generally to systems andmethods for modulating tissue through the delivery of energy. Tissuemodulation/stimulation, which includes nerve or neural modulation, cancause for example, inhibition (e.g. blockage), excitation, modification,regulation, and/or therapeutic alteration of activity and patterns ofactivity. These changes can occur in the central, peripheral, orautonomic nervous systems. Tissue modulation may include providingenergy to the tissue to create a voltage change, and in the case of anerve can be sufficient for the nerve to activate, or propagate anelectrical signal (action potential(s)). Nerve modulation/stimulationmay also take the form of nerve inhibition, which may include providingenergy to the nerve sufficient to prevent the nerve from propagatingelectrical signals or “nerve block”. Nerve inhibition may be performedusing approximately continuous or ongoing application of energy, and mayalso be performed through the application of enough energy to inhibitthe function of the nerve for some time after the application. Otherforms of neural modulation may modify the function of a nerve, causingfor example a heightened or lessened degree of sensitivity. As referredto herein, modulation of a nerve may include modulation of an entirenerve and/or modulation of a portion of a nerve. For example, modulationof a motor neuron may be performed and may only lead to changes in thoseportions of the neuron that are proximal to, or distal to, the locationto which an energy field is applied.

FIGS. 1a and 1b show one embodiment of the invention which is a novelsystem and method for improving the selective modulation of targetedbiological tissue such as various components of the nervous system. FIG.1a shows a cutaneous surface electrode 14 located near a tissue target12, such as the posterior tibial nerve. A selective increase in neuralexcitability (i.e., reduced stimulation threshold) of the tissue target12 is achieved by placing a biologically-compatible ‘implant’ 10 insufficiently close proximity to the targeted neural tissue 12, as shownin FIG. 1b (close-up of the target 12 of FIG. 1a , which shows theimplant 10 embedded within the epineurium). Under certain circumstances,presence of this implant 10 can also increase the amount of electricalcharge or energy needed to activate non-target nerves 16 a, 16 b locatedin the vicinity of the target, thereby supporting increased stimulationselectivity or specificity (note: anatomically, 16 a and 16 b areposterior tibial vein and artery blood vessels, however in this examplewe are treating these as non-target nerves for purposes ofillustration). In most embodiments, the implant 10 (or implantablepassive component “IPC”) is at least partially electrically conductive,and has at least one conductive portion which may be a conductivesurface. The conductive portion is preferably a highly conductivematerial for promoting electrical nerve activation. The IPC is notphysically connected to any electrical power source but rather ispositioned to modify the electrical field, energy, or power that affectsthe targeted (nervous) tissue 12. The IPC may be physically secureddirectly to nerve tissue or surrounding connective tissue, for example,by a suture. The IPC may have a connector portion to assist with itsimplantation and securing. In one embodiment, the IPC serves to modifythe field generated by a cutaneously located stimulator 14 such as anelectrode that receives stimulation signals from an external nervestimulator (also termed neurostimulator or pulse generator) 18.

In another embodiment of the invention which can be used, for example,in order to test, adjust, and select therapy parameters, the systemcomponents and target tissue may be simulated using a software modelcomprised of computer code which can be implemented by a processor in acomputer, for example, a finite element model of the human lower leg. Ananalogous finite element model of the human lower limb can approximatethis scenario by setting the virtual surface electrode at a constantcurrent (e.g., −1 mA, cathode) and the proximal cut surface of thevirtual leg as the return (anode). However, in the real world, thereturn electrode can be placed anywhere on the patient, or alternativelycutaneous (surface) stimulation can be delivered by a pair of electrodes(bipolar configuration). The electrode 14 may be bipolar having bothanode and cathode portions (e.g., concentric ring electrodes), withnon-conductive material between, or it may be monopolar with the returnelectrode located at a distal location. FIG. 1a shows an electrodeconfiguration, where the electrode 14 is placed at the level of skin 20near the IPC 10.

FIG. 1c shows an alternative embodiment of the enhanced nervestimulation system having at least two surface electrodes 22 a, 22 bthat are placed on the skin surface 20 in a bipolar configuration whereone electrode serves as anode (+) and the other as cathode (−).Although, in this example, stimulator lengths L1 and L2 and stimulatorwidths W1/W2 are set to 5 mm and 2 mm, respectively, the widths andlengths of the two electrodes may be different, and the electrodestimulators may also be of different shapes (rather than both beingrectangular). The IPC 10 may be implemented as a semi-annular or annularcuff-type electrode which is embodied as a hollow cylindrical cuff thatpartially or completely wraps around a nerve 12, and is in close contactwith the outer surface of the nerve. The inter-electrode (“IE”) distanceis indicated by the D1 double-headed arrow located between the twostimulators 22 a, 22 b, while depth (distance between the surfacestimulators and the IPC) is represented by the D2 double-headed arrow.An electrical source 18 is connected to a pair of cutaneous electrodesthat are affixed to a patient's skin 20 near at least one IPC 10. Theelectrodes may include at least one anode electrode 22 a and at leastone cathode electrode 22 b so that current flows through the tissuebetween the at least two electrodes and also provides electricalstimulation to target tissue such as nerve 12, and is influenced by atleast one IPC, positioned within the patient. As will be shown, certaincharacteristics of the therapy system (and the corresponding parametersof the model) can influence the ability of the external stimulators 22a, 22 b to stimulate the nerve 12. For example, a) the widths W1,W2 andlengths L1,L2 of the surface electrode stimulators 22 a, 22 b, b) thedistance D1 between the two stimulators relative to the length of theIPC, c) the distance D2 between at least one stimulator and the IPC, d)the alignment between the edge of at least one stimulator and at leastone edge or “end” of the IPC, e) the distance between the IPC and thenerve, and f) the conductivity of the IPC, can all contribute toenhancing the electrical modulation of nervous tissue 12. Other factorssuch as the thickness, shape, and orientation of the IPC relative to atleast one stimulator, may also alter the excitability of the targetednerve. The system shown in FIG. 1c , illustrates both how it may beimplemented physically, when used to modulate nerve activity of apatient, as well as how it may be simulated as a computer model which iscalculated by a processor in order to test/assess, adjust, and selecttherapy parameters. In this embodiment, the IPC was modeled as a hollowcylindrical shell placed around and including contact with the outersurface of the nerve.

An embodiment of a method for clinically implementing the stimulationsystem may involve an assessment process which may be termed IPCassessment process, when an IPC is used. The initial step of the processcan include creating a computer or physical model (or mixture of thetwo) which simulates, for example, at least one stimulator, the patientand patient tissue, at least one of a target and non-target tissue, andeither no IPC or at least one IPC. When two simulations are compared,one in which the IPC is present and one in which the IPC is absent, thenthe two modeled results may be compared in order to assess the effect ofthe IPC. In the next step, the model can be adjusted to simulate how achange in each modeled parameter can affect the stimulated tissue, andaccordingly suitable stimulation protocols and parameters may be derivedfor subsequent use in a patient. In a following step, the model andsimulated results are then used to customize an improved stimulationsystem for use with an individual patient. The model parameters can beadjusted based upon patient measurements. For example, patientmeasurement may include structural and anatomical measurements obtainedby physically measuring characteristics of the patient, such as byobtaining sensed data including imaging data related to light/laser,ultrasound, MRI, x-ray or other imaging modality. Patient measurementsmay also include functional measurements of impedance, bloodflow (e.g.infrared spectroscopy measurements), EMG, data related to muscle (e.g.bladder) contraction, data related to bladder capacity, and the like.The IPC assessment process, such as that just disclosed, can be realizedin steps 34 and/or 48 of FIG. 17, and/or this process may be donewithin, before, or outside of, the other steps shown in the figure.Patient measurement data can also be used to adjust stimulation protocolparameters and system components (e.g. IPC shape), used during therapy,according to individual patients. This can be done to improve therapyand may occur during a step of initial therapy assessment, for example,as in step 250 of FIG. 22c . Patient measurements may be usedintermittently (e.g., every 6 months to one year of maintenance PTNstimulation) to confirm proper stimulation settings are maintained orrequire modifications.

A number of advantages of one aspect of the invention can bedemonstrated by computational models. The simulations support the ideaof selectively enhancing neural excitability by manipulating theextracellular potential gradient that is generated along the targetednervous tissue by electrical stimuli. This voltage gradient may becharacterized according to a model that is widely referenced in theliterature to predict the relative neural excitability (Rattay, F.(1989). “Analysis of models for extracellular fiber stimulation.” IEEETrans Biomed Eng 36(7): 676-682). This is referred to as the ‘activatingfunction’ (AF) and is defined as the second spatial derivative of theextracellular potential along an axon. In one computer model implementedas computer code to be processed by a computer with a processoraccording to the invention, the model allows a user to alter modelledparameters such as the length, position, shape, thickness, andconductivity of at least one IPC, distance from the IPC to a nerve,parameters for characterizing a nerve and surrounding biological tissueincluding, for example, electrical conductivity, distance of the IPCfrom at least one stimulator, the shape of the stimulator, additionalstimulators that may be used, the 3 dimensional distances between thestimulators, and modes of stimulation such as monopolar or bipolar andwhether a simulated signal generator utilizes a stimulator as cathode oranode in the provision of simulated stimulation signals. The output ofthe model can include results such as the activating function of anerve.

The simulated data that will be shown herein were obtained using alimited set of stimulation protocols (e.g., a single steady-statepulse). Although the system may often operate linearly, in order toenable stimulator-IPC pairs to operate well when using a larger set ofstimulation protocols, the system configuration and stimulator+IPCpairings may have to be adjusted (especially for very high frequencystimuli, such as, for example above 1 kHZ). The modelling can berepeated for a range of alternative stimulation signals (e.g.,frequencies, pulse shapes, polarities, and durations) and the systemconfiguration can be adjusted to accommodate these. Alternatively, onlystimulation signals empirically determined to be successful for a givensystem configuration can be used during the provision of stimulationtreatment. Additionally, look-up tables may be derived for differentstimulation signals and system configurations, so that the systemcomponents can subsequently be easily selected or adjusted appropriatelyfor a particular therapy. The data of the lookup tables may be used todetermine the characteristics of IPCs and stimulators according to thestimulation signals/parameters, and geometries of system components. Theadjustment/assessment of the system configuration can occur in step 48of FIG. 17, or step 250. The influence of non-conductive portions of theIPC on nerve activation can be modeled as well.

The computationally derived simulation data shown in FIGS. 2a -8, 9 b,and 9 c were obtained by implementing a 3-dimensional finite elementmodel that consisted of a surface electrode(s), a peripheral nerve(endoneurium, perineurium, and epineurium layers), an IPC (cuff-typehollow cylinder or solid rod), biological tissue (dermis, fat, muscleand bone), and a large saline bath. Electrical stimuli were applied ineither a monopolar or bipolar fashion. Monopolar stimulation (modeled asper FIG. 1a ) was achieved by setting the surface electrode at the skininterface as the cathode and the surface of the other anatomical objects(e.g., distal cut-end of leg) as the anode. For bipolar stimulation(modeled as per FIG. 1c ), one electrode was set as the cathode and theother as the anode. All electrical conductivity values were obtainedfrom the literature (Yoo and Durand, Selective Recording of the CanineHypoglossal Nerve Using a Multi-contact Flat Interface Nerve Electrode,IEEE Trans Biomed Eng, 2004). The resulting extracellular potential(within the endoneurium region) obtained from the finite element modelwas used to compute the AF of individual nerve fibers. In MATLAB thiswas calculated as the second spatial difference of extracellularpotential.

In the absence of an IPC, the electrical stimulation signals provided bythe surface electrodes would normally stimulate the neural target tissue12, and any non-targeted nerves within close proximity to the surfacestimulator. It is an advantage of the current invention to provide theIPC to increase neural excitation of targeted nerve(s), and therebyeffectively modulate one or multiple neural circuits that producetherapeutic effects. Although the exact mechanisms for the novelphenomenon which is the basis of this aspect of the system and methodare not completely understood it may be helpful to conceptualize thesystem as follows. In one embodiment, the IPC may act to modify theextracellular electric potential generated by the surface electrodes, inorder to focus the electrical field (i.e., act as a “lightning rod”),and thereby “enhance” the second spatial derivative of this field alonga given target nerve. This enhancement can be seen in relation tochanges in the nerve's activating function (AF). The AF is commonly usedto quantify the excitation of nervous tissue. In this manner the presentinvention may serve to provide several advantages such as focusing thefield toward an intended tissue target and away from adjacent tissue inorder to produce improved therapy with less stimulation-evoked sideeffects. Another advantage is that the system and method permits theelectrical therapy to use less power, at one or more stimulators, inorder to supply the therapy and obtain a given effect that is either notnormally attainable without more power, or which may not be attainableat all in the absence of the IPC. Using less power at the stimulationsite can also provide other advantages such as greater patient comfort.

Further advantages may be obtained if the IPC physical characteristicsare configured for improved performance, such as may occur, in variousembodiments, as part of step 48 of FIG. 17, or step 250 of FIG. 22c .For example, as will be shown, the IPC can provide larger improvementsin performance when it is of an appropriate size, shape, material, andelectrical property (e.g., higher conductivity than surrounding tissue).When configured according to certain considerations (e.g., size andlocation of at least one stimulator), the presence of the IPC 10 canreduce the net activation threshold of the targeted neural tissue. The“modification” of a stimulation field, according to the currentinvention, may include functionally modulating (e.g., re-directing,blocking, focusing, relaying, shaping, and/or otherwise having an effecton) the stimulation field so that the energy that reaches the targetedtissue enhances the effects of the applied stimulus to a greater degreethan what may be achieved in the absence of the IPC.

One embodiment of the invention comprises implanting an IPC as shown inblock 30 of FIG. 17 (e.g., metal nerve cuff surgically placed partiallyor fully around a specific nerve branch) that will be used inconjunction with various transcutaneous, percutaneous (e.g., needleelectrode), implanted, or other electrical stimulation devices, such asin step 36. These may include conventional transcutaneous electricalnerve stimulation (TENS) devices, implanted multi-contact leadelectrodes (e.g., Medtronic Interstim device), intravascular nervestimulation systems, implantable spinal and neurostimulators, and deepbrain stimulation systems. Various physical parameters of the IPC (e.g.,shape, length, width, thickness, density, curvature, material(s),resistivity/conductivity, relative permittivity) may also be used toshape, enhance and/or otherwise modify fields, and the parameter may beset or adjusted in block 34 in relation to at least one stimulator (i.e.“stimulator-IPC pairing”). In embodiments, the fields may be produced byelectrical stimulators, sound stimulators, or magnetic stimulators, suchas those used in transcranial magnetic stimulation (TMS). When used withmagnetic stimulation devices, the IPC may be shaped, positioned, andoriented, relative to the 1 or more coils that generate one or morestimulation fields. When the IPC is used with TMS stimulators, themethod and system may be referred to as enhanced TMS (eTMS). Whenrealized as part of an eTMS embodiment, the IPC may be constructed usingmaterial with lower electrical conductivity than that used for eTENS. Inan embodiment, the electrical source 18 of FIG. 1c may be replaced by amagnetic source which utilizes magnetic coils as stimulators 22 a, 22 b,(and which may be separated from the IPC by distances represented byparameters termed D2+D3) to provide a magnetic field such as atime-varying magnetic field. When the setup of FIG. 1c is realized as amodel, with the electrical source 18 replaced by at least one magneticsource generator, additional model parameters can be related to thestrength, orientation, distance (e.g., D2/D3), 3-dimensional location,and shape of one or more magnetic coils. Use of a magnetic stimulatorwith at least one coil 152 (which can be realized for example bystimulation device 400′ of FIG. 24c , or 50 of FIG. 18a ) is shown inrelation to providing vagal stimulation of a patient, by stimulatingImplant #3 142 c, in FIG. 21.

The following are non-limiting definitions for several terms that willbe used in this disclosure which are provided to facilitatecomprehension of the invention. In parts of the disclosure the terms maybe used slightly differently as should be evident in those parts.

Targets.

Targets for enhanced excitation may include any anatomical component ofthe human nervous system. The activation of targets may be used tomodulate neural circuits or reflexes to achieve a desired clinical ortherapeutic effect. These may include one or multiple nerves of theperipheral nervous system or a sympathetic nerve chain and/or all of theassociated structures and nerves in communication with the sympatheticnerve chain. Certain targets may be very advantageously targeted by thecurrent invention, such as targets that move or rotate or targets whichare small. For example, it may be easier to stimulate an IPC which hasbeen implanted in a portion of the eyeball which is coupled to astimulator that sits outside of the eyeball, than to attempt tochronically implant an electrode that is capable of transmitting poweralong a path that requires the electrode to remain fixed and unbrokenover a period of time. Another example is a target which may be withinthe vestibular system, or a facial or cranial nerve that is prone tomovement which would make the use of a relatively larger, fixedelectrode difficult. Another target may be in the foot, or near anankle, where using a small IPC with an external stimulator will not beprone to the same damage or risk of electrode migration of an electrodewhich is tethered to a stimulator and which experiences shearing andpulling forces. As will be disclosed, targets for targeted stimulationusing IPCs can also be various types of tissue such as muscle or bone.

Conditions.

The medical conditions that can be treated by methods of the presentsystem and method include a host of conditions such as, but not limitedto, skeletal, immunological, vascular/hematological, sleep related,metabolic, muscular/connective, neurological, visual,auditory/vestibular, dermatological, endocrinological, olfactory,cardiovascular, reproductive, sexual, urinary, voiding, psychiatric,gastrointestinal, respiratory/pulmonary, inflammatory, infectious(bacterial, viral, fungal, parasitic), traumatic, iatrogenic, pelvicfloor conditions and dysfunctions, drug induced and neoplastic medicaland surgical conditions. Other conditions for which the technology maybe applied are disclosed throughout this specification.

Treatment.

As used herein, the term “treating” a medical condition encompasses, forexample, therapeutically regulating, preventing, improving, alleviatingthe symptoms of, reducing the effects of, and/or diagnosing a medicalcondition. As used herein, the term “medical condition” encompasses anycondition, disease, disorder, function, abnormality, or deficitinfluenced by the nervous system. Further, the methods of the presentinvention can be used to treat more than one medical conditionconcurrently. Non-limiting examples of medical conditions that can betreated according to the present invention include genetic, skeletal,renal, dental, immunological, vascular or hematological, muscular orconnective tissue, neurological, ocular, visual (treated with or withoutconcurrent visual stimulation), auditory or vestibular, tinnitus(treated with or without concurrent auditory stimulation),dermatological, endocrinological, olfactory, cardiovascular,reproductive, urinary, fecal, psychiatric, gastrointestinal,respiratory/pulmonary, neoplastic, or inflammatory medical conditions.Further, the medical condition can be the result of any etiologyincluding vascular, ischemic, thrombotic, embolic, infectious (includingbacterial, viral, parasitic, fungal, abscessal), neoplastic,drug-induced, metabolic, immunological, collagenic, traumatic,surgical/iatrogenic, idiopathic, endocrinological, allergic,degenerative, congenital, or abnormal malformational causes.

Further, treatment may include stimulation. Stimulation may include anytype of modulation of physiological or biological related activity. Thusstimulation and modulation may be used interchangeably when theintention is to describe the influence of a generated field upon humantissue. Other conditions for which the technology may be applied for“treatment” are disclosed throughout this specification. Treatment mayalso include providing benefit to a human by producing a desired effect,such as, stimulation provided to promote weight loss.

Implant Component.

The implanted component that is often referred to as an implantablepassive component “IPC” may be as simple as a passive conductiveelement. The IPC may also have securing structure such as flaps that canbe mechanically folded over to situate and secure the IPC in place. TheIPC may have a least one suture hole for securing the IPC in place. TheIPCs may be of many shapes and sizes and may have physical dimensionsthat are configured based upon the tissue target where it will be used,the distance of the target from the stimulator, and the size of astimulator, as well as other factors. The IPC may have conductive andnon-conductive surfaces and portions, as well as more than oneconductive portion, which are not electrically continuous with adifferent conductive section. When an IPC has circuitry that is drivenby electrical or magnetic fields or otherwise has active components suchas circuitry then the IPC becomes an implantable active component “IAC”,such as a neurostimulator that is externally powered or self-powered byinternal power. The IPC may be configured so that permanent implantablepulse generators can be attached to the IPC in the case where the IPCwill be used, or subsequently used, as a nerve cuff. In this case theIPC functions as an electrode of an implanted neurostimulator. Allowingan IPC to be connected to an implantable neurostimulator can beadvantageous such as may occur if cutaneous stimulation provided incombination with an IPC is found to be inefficient, or becomesinefficient over time and an implantable stimulator will then be used toprovide stimulation signals to the IPC without having to implant anotherelectrode. In various embodiments of the invention an IPC, IAC, nervecuff, or implantable neurostimulator may be used to provide stimulationsignals to target tissue. It should be understood that these examples,are non-limiting. For example, in the case of selective nerve branchstimulation an embodiment of the invention may be approximately realizedusing any of the following: IPC, IAC, self- or externally-poweredneurostimulator which works with a multi-contact nerve cuff.

Stimulator.

A stimulator is a system component that supplies a stimulation signal totissue. A stimulator may refer to a tens electrode, an electrode leadhaving at least one electrical contact, one or more electrode contacts,nerve cuff, a multi-contact electrode, a spinal stimulation lead, amagnetic coil, a sound, vibration, or light transducer, or othercomponent for emitting energy for modulating tissue. The stimulatortransmits at least one stimulation signal to tissue that is provided by,for example, an electric, magnetic, or sonic signal generator, a pulsegenerator, or an implanted a neurostimulator. In a neurostimulationsystem, it is generally understood that the neurostimulator will supplya stimulation signal to a stimulator which may be realized as at leastone electrode.

Stimulator-IPC Pairs.

At least one stimulator and at least one IPC can be selected or adjustedso that these work well together in the intended manner to provideenhanced, targeted stimulation to a tissue target, compared to thatwhich occurs when an IPC is not used. For example, a stimulator-IPC pairmay include a stimulator that has a physical dimension set in relationto the IPC so that the two are well “matched”. The physical dimension ofan IPC or (at least one) stimulator can include, for example, the shape,size, length, orientation, and thickness of at least one conductiveportion. Further, a stimulator—IPC pair may be matched by beingconfigured so that the stimulator and IPC have at least one edge that isaligned, which has been shown, in some instances, to provide forincreased enhancement of effects on the target in the stimulation field.

Electrical Fields and IPC-Stimulator Orientations.

Various types of signals and fields may include electrical, magnetic, orboth (and can also be (ultra-)sound, vibration, or laser/light). In someembodiments, a modulation signal may include a moderate amplitude andmoderate duration, while in other embodiments, a modulation signal mayinclude a higher amplitude and a shorter duration. Various amplitudesand/or durations of field-inducing signals which are provided bystimulators such as 88, 90 may result in functional (i.e.,super-threshold) modulation signals. Whether a field-inducing signalrises to the level of a modulation signal can depend on many factors(e.g., distance from a particular nerve to be stimulated; whether thenerve is branched; orientation of the induced electric field withrespect to the nerve; type of tissue present between the electrodestimulators and the nerve; size of the IPC; suitability of pairingbetween the stimulator and IPC, etc.). Whether a field inducing signalconstitutes a modulation signal (resulting in an energy field that maycause nerve modulation) or a sub-modulation signal (resulting in anenergy field not intended to cause nerve modulation) may be affected bythe proper alignment (e.g., x-, y-, and/or z-axis orientation and/ordisplacement) of at least one edge of the IPC and the stimulator. Bothmodulation and submodulation fields may be created as part of theinvention.

Stimulation/Treatment/Therapy Protocol.

Protocols can be implemented under control of a closed or open loopalgorithm implemented by processing circuitry of an implantableneurostimulator, under direction of a physician, as adjusted or selectedby a patient during therapy, or otherwise. Many of the protocols thatare described herein for implantable neurostimulators are understood toequally well accomplished by a doctor in a clinic or a patient at home,with appropriate modification, without departing from the spirit of thedisclosed invention. Any protocol that is disclosed as being carried outby an implantable device with electrodes may also typically beconsidered a candidate for being accomplished by a partially or fullyexternal stimulation system, and vice versa. It is generally understood,that a step of a method of stimulation disclosed herein can be embodiedwithin a stimulation protocol accomplished by, for example, a fullyimplantable neurostimulation system. A therapy/treatment protocol mayinclude not only a stimulation protocol, but also a sensing protocol andmay also include rules and algorithms for how to process sensed data andhow to change stimulation parameters based upon the evaluation resultsof sensed data. The therapy protocol may also include the provision ofconcurrently supplied drug therapy under control of a device or by thepatient.

FIG. 2a shows a graph of the results of a modeled AF of a single axonlocated within the posterior tibial nerve (PTN) in response to asimulated current pulse (−1 mA) applied by a surface electrodestimulator. A computational finite element model was used to assessenhancing the excitability of the PTN. The model consisted of a3-dimensionally reconstructed human lower limb with a surface electrodeplaced over the PTN. The anode was the proximal cut surface of the lowerleg (farthest from the surface electrode). As indicated in FIG. 1a , theIPC 10 is simulated as a highly conductive material placed in closeproximity to the nerve and was modeled as a rod with diameter=0.2 mm andlength=5 mm. The graph shows the simulated effects of varying thedistance between the IPC 10 and the target nerve 12 on the calculatedAF. In all simulations, the maximum AF value was used to determine theexcitability of the targeted nerve. The AF was calculated for a seriesof simulations, where the distance between the implant and the PTN wasdecreased from 8 mm (outside the epineurium) to 0 mm (direct contactwith nerve bundle, perineurium). The results of FIG. 2a indicate thatthe IPC—for the given length, diameter, shape, and conductivity—beginsto enhance neural excitability at a distance of approximately 3 mm fromthe nerve. This enhancement continues to increase to almost 8-fold whenthe implant is embedded within the connective tissue layer surroundingthe nerve itself (the “epineurium”). The graph suggests that, using thissetup, a steep benefit is gained as the IPC-to-nerve distance is reducedbelow 2 mm. Modifications to the modelled or real world systemconfiguration (e.g., size and location of the stimulator, IPC or nerve)may change the shape of the graph. However, in a typical embodiment ofthe IPC, the conductive component will likely be implanted to residealong the nerve which it stimulates such that its entire length isadjacent to the nerve. In an embodiment the IPC is implanted to resideapproximately parallel to the target nerve and is secured at two or moresites, such as both at its proximal and distal end, in order to determigration and rotation.

FIG. 2b shows the simulated results reflecting changes in the AF as thedistance between the IPC and nerve combination (“Implant+Nerve”) and atleast one of the stimulating electrodes is increased. The effects of theimplant on neural excitability were quantified by comparing the maximumAF between the control case (labeled as “no IPC” in the figure) to thecase where an IPC was placed in close proximity to the nerve (i.e.,inside the epineurium). The implant caused a 184% increase in AF for anerve located 7 mm from the skin surface (i.e., site of stimulatingelectrode). Compared to the nerve without an IPC (labeled as ‘no IPC’,dashed line), the AF is consistently greater with the IPC placed closeto the nerve (labeled as “IPC inside epineurium”, solid line). Further,at a stimulator-to-IPC distance of 30 mm the AF achieved by the IPC issimilar to the AF achieved at a stimulator-to-nerve distance of under 10mm, when no IPC is used. Benefit may be also obtained at greaterdistances beyond those shown in the graph (and other graphs disclosedherein, which are not meant to be limiting).

Repeated computer simulations at stimulator-to-nerve distances of up to3 cm (as per FIG. 2b ) showed the AF drops precipitously over theinitial 15 mm and asymptotes at about 25 mm. This trend is the same forboth cases (with and without the IPC), but clearly shows the IPCenhances neural excitability at all nerve depths.

FIG. 3a shows modeled results of the “relative excitability” of thetarget nerve, calculated as the ratio of the AF of an “IPC present(rod)” condition compared to an “IPC absent (no rod)” condition (seeFIG. 2b ). The positive slope indicates that the enhanced neuralexcitability effect due to the IPC is relatively greater for nerveslocated further away from the surface electrode stimulator. FIG. 3asimulation results suggest that stimulation amplitude required fortranscutaneous nerve activation can be significantly reduced using anIPC. FIG. 3a data suggest that the stimulation amplitude at the surfacemay be reduced to approximately 25-50% of the original stimulationintensity, since the relative excitability (RE) moves from about 1.8× toabout 4×.

FIG. 3b shows the effects of electrical conductivity of the IPC(rod-type implant) on the RE (relative excitability) of the target nerveEnhancement of neural excitability (quantified as the relativeexcitability) is maximally achieved when the electrical conductivity ofthe IPC equals or exceeds 4E+2 S/m (or approximately 1.00E+3 on thegraph). This lower boundary corresponds to an electrical conductivitythat is approximately 5 orders of magnitude greater than that of thenerve (e.g., epineurium). These results suggest that mosthighly-conductive metals would serve as appropriate IPC materials forenhancing TENS, with platinum or gold serving as good candidates. Ofcourse various conductive alloys, and semi-conducting material which maybe suitably doped, may be used to create at least portions of the IPC.

FIG. 4a shows the effects of nerve depth (from skin surface) on theinter-electrode distance between two surface electrode stimulators(bipolar stimulation, see FIG. 1c ). The effect was quantified by themaximum AF calculated from computer simulations of the rat PTN thatsimply included surface stimulators and did not also incorporate thesubcutaneous placement of an IPC. These results are relevant totranscutaneous stimulation embodiments of the invention having bipolarsurface electrodes. The finite element model, having a monopolar setupwhich is illustrated in FIG. 1a , and which was used to generate resultspresented in FIG. 2a, 2b and FIG. 3a, 3b , was modified to approximatetranscutaneous electrical stimulation of the PTN in a rat. Thismodification simply involved scaling all components of the model to thatof rodents: nerve radius (0.38 mm), nerve depth (1.5 mm), skin thickness(0.46 mm), pair of surface electrodes (2 mm×1 mm) comprising the anodicand cathodic electrodes. The results of this computer model indicatethat optimal nerve activation (maximum AF) is achieved when theinter-electrode (stimulator) distance approximates the depth of thenerve from the skin surface (1 to 3 mm). The maximum AF at aninter-stimulator distance of 1 mm showed low neural excitation for allnerve depths. This suggests the electrical current is effectivelyshorted between the cathodic and anodic electrodes. When an IPC is used,the results may change due to the physical dimensions of the IPC andstimulators, both in absolute and/or relative terms.

These results indicate that deeper nerves are more easily activated bybipolar electrode pairs when greater separation is used. In oneembodiment of the system 6, shown in FIG. 1c , the inter-stimulatordistance D1 should be varied proportionately to the distance between asurface stimulator and the nerve D2. The effects relating to spacing ofthe surface electrodes, in relation to depth of stimulated tissuetarget, may be applicable whether an IPC is used or not. In general, ifthe electrodes are placed closer together the area of highest currentdensity will be relatively superficial, while further spaced electrodeswill cause the current density to be higher in deeper tissue. Electrodestimulator size will also change the current density, with largerelectrodes decreasing current density relative to smaller electrodes.Accordingly, placing a smaller electrode closer to the nerve or IPC witha larger electrode (dispersive electrode) remote from (further away) thetissue target should cause the current density to be higher near thesmaller electrode (near the tissue target). Cutaneously appliedelectrode size and position characteristics will therefore alter thecharacteristics of the current density and path. When an IPC is used,this relationship must also be considered in relation to thespecifications of the IPC. If the IPC and stimulators are “paired” withrespect to selected characteristics, in order to increase theeffectiveness of stimulation, then these pairing should be consideredwith respect to factors such as depth of the IPC/nerve, and may be partof step 250. Stimulation of a deeper nerve may require a larger spacingof the surface stimulators, which may, in turn, require an increasedlength of IPC. These, as well as other considerations may be used in theadjustments to the current invention stimulation systems and methods ofproviding therapy to a patient.

FIG. 4b shows a graph of computationally generated simulation resultsexploring the effect of IPC thickness. These IPC physical characteristicresults are relevant to, and can be used to guide, the adjustment theIPC shape characteristics. Instead of the IPC modeled as a solidcylindrical rod placed within the epineurium (FIG. 1b ), the IPC wasmodeled as a simple cylindrical cuff wrapped around the nerve (FIG. 1c). This practical and simple design is currently used for manyimplantable nerve cuff electrodes. With the cuff length set at 5 mm, thethickness of the cylinder was varied from zero (reflecting no IPC) up to1.2 mm. The results of this study suggest that neural excitability ismaximally enhanced by thinner IPCs (e.g., 20 μm thickness), at least inthe case of implants with a length of 5 mm and a relatively shallownerve depth of 2 mm. Various manners of modifying the IPC physicalcharacteristics may also serve to increase excitability, aside fromadjusting the shape characteristic to create a thin IPC. For example,the physical characteristics can be selected so that the IPC created ofa mesh, or using material with different electrical conductivity, mayalso be simulated to assess performance and/or selected for use toprovide improved excitability. In one embodiment, using a material suchas mesh that decreases the mass of the implant, increases flexibilityand adaptability of the IPC, and increases patient comfort, or has otheradvantages may improve the performance of the system and decrease thelikelihood of adverse events. Further, it should be noted that, for thesimulation signals and parameters investigated in the study, an IPCthickness of less than 0.3 mm increased AF, while a thickness above 0.3mm was found to reduce neural excitability. When using a bipolarstimulation configuration, a therapy system may rely upon different IPCthickness to “selectively” activate targeted nerve(s). Since increasingthicknesses of the IPC above a certain dimension (e.g., IPCthickness=0.3 mm) was found to increase the activation threshold, in oneembodiment, an IPC of increased thickness above that threshold thicknesscan be used to suppress activation of adjacent non-target nerves at thisparticular nerve depth. In combination with this, a thinner IPC,configured to increase the excitability of a nerve, can be used on thetarget nerve.

FIG. 4c is a graphical representation showing data from computersimulations involving a monopolar stimulator used to activate aperipheral nerve placed at varying depths. In this embodiment, thenormalized MAF (maximum activating function) increased as the thicknessof the IPC (cuff-type implant) was decreased, at nerve depths (ND) of 2mm and 3.5 mm. The enhanced effects of reducing IPC thickness at theserelatively shallow nerve depths corroborate our simulations that usedbipolar stimulators (FIG. 4b ). However, at deeper nerve depths (5 mmand 10 mm) the normalized MAF increased as the IPC thickness wasincreased. This enhancement in neural excitability indicates thatgreater overall electrical conductivity of the IPC may play an importantrole for nerves located relatively farther from the skin surface. As aresult, this suggests that eTENS activation of nerves at relativelygreater nerve depths may be further enhanced such as by using differentIPC material (e.g., higher electrical conductivity), and largerdimensions (e.g., thickness or length, see FIG. 8).

FIG. 5a shows a graph of simulated results of the combinations ofinter-electrode distance and IPC length for achieving effectiveperipheral nerve activation (i.e., lowest activation threshold). In amodel of rat PTN stimulation (e.g., as per the set-up of FIG. 1b ) thepeak of each trace corresponds to an IPC length that is very similar inphysical dimensions to the inter-electrode distance. The data suggestthat enhancement of neural excitation is improved when theinter-electrode distance approximates, or is a little less than, thelength of the IPC, for the range of IPC lengths shown and for thestimulation waveform and protocol used. Changes in the AF were studiedin response to varying the length of the implant, from 0 mm (no implant)up to 15 mm. These simulations were repeated for differentinter-electrode distances: 2.75 mm, 5 mm, and 7.5 mm. For each giveninter-electrode distance and bipolar configuration, the maximum AF wasachieved when the implant length approximated this distance (e.g., 8 mmimplant length for an inter-electrode distance of 7.5 mm). Accordingly,in a system for providing eTENS therapy 6 the IPC length can be set inproportion to the distance between at least 2 stimulators, such as beingequal to, or slightly less than, or having other relationship to thedistance between the two electrodes.

In FIG. 5a , the zero mm data points are equivalent to not using any IPC(“no IPC”). Accordingly, any system and method which utilizes an IPCthat increase the AF above the no-IPC condition can provide enhancednerve excitability. Further, any AF which is below the no-IPC condition,for example, IPC lengths of about 12 to 15 mm when the inter-electrodedistance is any of those tested in the figure, will serve to decreasethe excitability of that nerve. Accordingly, providing IPCs that causedecrements in excitability to non-target nerves may provide a strategyfor further increasing the selective activation of a targeted nerve.Even when not discussed explicitly, in all other figures of thisapplication, when the AF drops below the no-IPC condition, the resultscould be understood to be relevant to providing greater selectivity oftarget nerve stimulation when the IPC is used with non-target nerves.

Additional computer simulations were also conducted using a singlemonopolar surface electrode that was aligned to the center of the IPC10. The width (W) remained the same, but the length was varied. Theanodic (return) electrode was modeled as being placed far away from theactive cathode. The results of this study showed that maximum AF (i.e.,lowest stimulation threshold) was achieved when the length (L) of thesingle electrode was larger than the IPC. In other words, when themono-polar electrode was sized to fit exactly in between the pair ofelectrodes in FIG. 1c the optimum activation was not found. While theresults of FIG. 5a , suggest that optimum nerve stimulation is achievedwhen the opposing edges of the IPC align (approximately) with those ofthe surface electrodes, this may be true for bipolar but not monopolarstimulation. It is likely that in one embodiment of a clinical system,the edges of the IPC and at least one electrode should be approximatelyaligned (e.g., spatial and angular alignment), while alignment of twoparallel edges may only improve bipolar stimulation. Initial data hassuggested that in the case of monopolar stimulation, increasedactivation is obtained when the monopolar electrode is longer than theIPC (data not shown). Accordingly, in one embodiment of the system whichuses a monopolar electrode, at least the length or width of thestimulator should be made to be larger than then IPC, and further onlyone edge of the IPC should be aligned with an edge of the stimulatorelectrode.

FIG. 5b shows a graph of computer simulations using the original humanPTN model (inter-electrode distance range: 2 cm to 8 cm) that confirmthe results of the rat PTN model translate to larger physicaldimensions.

FIG. 6a shows a data from a computer model that simulated eTENS using amonopolar surface electrode. When both edges of the electrode (length of1 mm along the nerve) and the IPC (nerve cuff length of 1 mm) arealigned (misalignment=0 mm), the AF is actually below that of TENSwithout any IPC. However, as the IPC is moved along the nerve, the AFbecomes approximately 1.25 times greater than that for conventionalTENS. In this example (nerve depth=2 mm), the ‘enhancing effect’ of theIPC persists even with an inter-edge gap (distance between the rightedge of electrode and the left edge of IPC) of up to 1 mm (i.e.,misalignment=2 mm). Beyond this misalignment, the IPC has negligibleeffect on neural excitability. Accordingly, in one embodiment of thesystem which uses a monopolar electrode, the alignment of the IPC andstimulator should be adjusted, for example, as per step 48 in FIG. 17,so that the inter-edge gap provides improved AF. The nerve depth in thisexample was only 2 mm and different relative excitability functionresults may be obtained when simulated for other nerve depths which canthen be used to adjust the clinical embodiments of the systems andmethods of the current invention.

FIG. 6b shows data from a computer model that is similar to FIG. 6a ,but with a longer IPC (nerve cuff length=5 mm). These results show thatif the IPC is longer than the surface electrode and that the electrodeoverlaps with the nerve cuff (misalignment up to 2.5 mm), the AF of thetarget nerve is enhanced by 1.4 to 1.8 times that of conventional TENS.Maximum enhancement is achieved (increased AF by 2.2 times) when theinter-edge gap (between the electrode and IPC edges) is between 0.0 mmand 1.0 mm (which occurs when the misalignment is about 3 mm). Atinter-edge gaps greater than 2.5 mm (misalignment above 5 mm), the IPCdoes not affect neural excitability. It should fairly easy to implementthe current invention during treatment with inter-edge gaps that produceat least 25% increase in excitability compared to when no IPC is used.Although the effects of IPC alignment at deeper nerve locations are notexplored here, initial results indicate the alignment effect may be lesspronounced for nerves further from the skin surface (similar to what isseen with nerve cuff thickness, FIG. 4c ).

FIG. 7 shows a graph of computationally generated results exploring theeffects of the electrical conductivity of the IPC on the relative neuralexcitability using monopolar stimulation (nerve depth=2 mm, IPCthickness 0.02 mm). For conductivity values above 9.43E+2, there isobserved enhanced neural excitation (as shown in FIG. 3b ). However, atelectrical conductivity values between 9.43E−4 and 9.43E−1 there isobserved negligible effects of the IPC (no change in relativeexcitability); whereas at conductivity values below 9.43E−5 there isobserved reduced excitation of the nerve on which the IPC is implanted.These findings suggest a novel system and method of increasing theselective activation of a targeted nerve in which a highly conductiveIPC is implanted on the target nerve. Additionally, a poorly conductiveIPC may be placed on or near one or more non-target nerves to deterunwanted activation. As with the other characteristics of the system,the proper conductive characteristics for one or more IPCs can beselected or adjusted based upon simulated modelling or based upon systemconfiguration including, for example, the number and position of IPC andstimulators which will be used during treatment.

FIG. 8 shows the relationship between the length of the IPC and thedepth of the nerve (ND). In this computational model, the IPC was anerve cuff with 0.02 mm thickness and the IPC+nerve was positioned at 4different nerve depths: ND=2 mm, 3.5 mm, 5 mm, and 10 mm from the skinsurface. For this example of monopolar stimulation, the data indicatesthat increasing the length of the IPC can markedly increase neuralexcitability. This ‘enhancement effect’ is more pronounced for nerveslocated further away from the skin surface. For shallow nerve depths (2mm), the effects of increasing the IPC length are diminished beyond 4mm, with the neural excitability increase showing a plateau atapproximately 1.5× of conventional TENS (no IPC). In contrast, at deeperlocations (10 mm ND), the AF continues to increase up to IPC lengths of9.5 mm, where the neural excitability reaches a 6.5 multiple ofconventional TENS. In an embodiment of the system and method ofproviding eTENS stimulation, the length of the IPC can be adjusted, asper step 48 in FIG. 17, in order to derive the desired increase inneural excitability. Additionally, in some embodiments, for deepernerves, longer IPCs should be selected to provide improved enhancementof neural excitability. Further for deeper nerve targets, increasing thethickness of the IPC may provide for increased excitability of thetarget nerve (FIG. 4b shows increased MaxAF at lower thickness, comparedto higher thicknesses, because that nerve target was relativelysuperficial).

FIGS. 9 a,b,c show the effects of an IPC on the recruitment propertiesof transcutaneous nerve stimulation. These results were obtained fromrat experiments (FIG. 9a ) and computer simulations (FIG. 9b,9c ). FIG.9a shows data supporting IPC enhanced excitability that was obtainedfrom in vivo studies in anesthetized rats. A monopolar surface(cathodic) stimulating electrode (5 mm×10 mm) was placed over the PTN ofthe left leg immediately rostral to the calcaneous (ankle bone). Thereturn electrode (anode) was connected to a needle inserted through theabdominal fat pad, ipsilateral to the active cathode electrode. A pairof de-sheathed stainless steel wires were inserted into the foot,ipsilateral to the cathodic electrode and connected to a low-noiseamplifier. This electrode was used to record the electromyogram (EMG)evoked by transcutaneous PTN stimulation. Results from one experimentare shown in FIG. 9a , which illustrates that the presence of the IPC 10around the PTN (immediately rostral to the ankle) lowers the nervestimulation threshold by 30% of that seen when no IPC was used. Thefigure characterizes the recruitment of foot EMG activity that waselicited by transcutaneous PTNS, with (solid line) and without an IPC(dashed line) placed around the nerve. The implant was implementedexperimentally as an aluminum cuff. The data indicate that the IPC 10 ofthe current invention can effectively (1) lower the stimulationthreshold (labeled “A” in the figure) for activating the PTN (2000 uAvs. 2800 uA) and (2) produce larger EMG activity (37 mV vs. 21 mV), asmay occur through recruitment of more PTN fibers, or improved coherentactivation, by transcutaneous stimulation. In addition to the thresholdoccurring at a lower amplitude of stimulation, the maximum foot EMGactivity in the no IPC condition never reaches the maximum attained inthe IPC condition. EMG serves as a proxy index to suggest the IPCimproves coherent synchronous activation or recruitment of a largertotal number of fibers, in response to nerve stimulation.

FIG. 9b shows a diagram of the computer model, which was used toinvestigate the effects of the IPC (implanted on target nerve “a1”) onthe neural excitability of non-target nerves (a2-a5 and a12-a15). FIG.9c compares the computationally derived activating function (i.e., nerveexcitability) of multiple nerves, where one (a1) has been instrumentedwith an IPC. As the length of IPC was increased from 0.1 mm to 4 mm, theexcitability of the target nerve showed a 50% to 100% increase in theAF; while there was little change in the excitability of non-targetednerves. Further, at IPC lengths of 10 mm to 60 mm, the excitationproperties of the targeted (a1) and non-targeted nerves begin to divergemore dramatically. The percent change in AF for target a1 reaches a peakat 20 mm (342% increase), while the remaining nerves exhibit a 40% to60% decrease in excitability beyond this IPC length. This data supportan embodiment of the system and method of providing eTENS stimulation,wherein the IPC is provided for a target nerve to increase thesensitivity to stimulation, and within certain ranges the IPC can alsoincrease stimulation specificity by decreasing the effect of theelectrical field on non-target nerves.

While the experimental data (FIG. 9a ) confirms enhanced neuralexcitation achieved by an IPC placed around the target nerve, thecomputer model results (FIG. 9b ) show that the IPC can concomitantlyreduce the excitability of surrounding (non-targeted) nerves.Accordingly, a single highly-conductive IPC may minimize anystimulation-evoked side-effects normally caused by unwanted activationof adjacent nervous tissue. While the mechanism for enhancedselectivity, at a given stimulation level, is not yet fully understood,it may be that the IPC provides a lower resistance path for theelectrical field and thereby decreases dispersion of the field aroundthe area of the IPC. As such, as will be disclosed later, embodimentsusing 1 or more IPCs may be used to shape, bias, deform, focus, or guidean electrical path (or magnetic field) through tissue. It may be thatwhen used in humans to stimulate different targets, the guidelines forproducing improved pairing can be different. For example, with longerIPCs than were tested here, the alignment of the stimulator edge may befound to improve pairing when aligned with the middle rather than theedge of an IPC. Both modeled and empirical results can be used toimprove stimulation systems using one or more IPCs. Additionally, withIPCs tested using lengths at least 1 cm, recent unpublished data fromthe laboratory of Dr. Yoo has indicated that longer IPCs are better andaccordingly, in an embodiment an IPC should be at least 1 cm long. In afurther embodiment, it may be that the IPC can be may be even longer ifthe nerve target is accessible across that length in order to provideimproved enhancement of stimulation.

Treatment of Incontinence and Related Disorders

A central use for the systems and methods of the present inventionrelate to treatment of chronic lower urinary tract dysfunction, such asoveractive bladder and detrusor underactivity related to urinaryretention. For simplicity the term overactive bladder (OAB) may be usedto refer to various types of voiding disorders and urologicaldysfunctions (e.g. pelvic floor disorders), without intending to belimiting. The following example embodiments of the invention for thetreatment of disorders are provided in the context that the embodimentsand principles can be generalized to tissue modulation treatment ofother disorders to provide various benefits.

FIG. 10a and FIG. 10b show various embodiments of enhanced nervestimulation systems, where selective activation of targeted nerves canbe achieved by placing an IPC 10 in close proximity to, in directcontact with, embedded within, or wrapped around, these nerve bundles.Depending on a specific therapeutic protocol, one or more IPCs can beused for enhanced transcutaneous nerve stimulation at one or more sites.In embodiments, the target nerves can include, for example, the pudendalnerve, pelvic nerve, posterior tibial nerve, medial plantar nerve,lateral plantar nerve, calcaneal nerve, saphenous nerve, sacral nerveroot and lumbar nerve root.

In FIG. 10a the urinary bladder 28 and urethra 29 are showndiagrammatically on the left side of the figure as innervated primarilyby nerve targets such as the pelvic 24 and pudendal 26 nerves, theelectrical activation of which can be enhanced by IPCs 10 a and 10 b,respectively. One embodiment of a system and method of selective pelvicor pudendal nerve stimulation may be achieved by providing therapyaccording to a therapy protocol to deliver electrical pulses using astimulator that is at least one of an intravesicle or intraurethralelectrode, or by using at least one electrode array. The stimulatorwould stimulate nerve targets for which IPC's have previously beenimplanted (e.g., pudendal nerve). This setup may allow for advantagessuch as permitting a stimulation electrode to migrate slightly while theIPC remains well situated with respect to the nerve target. Thestimulator may be permanently implanted or temporarily inserted insimilar manner as urethral catheterization (e.g., as in cases ofspina-bifidda, neurogenic bowel or bladder dysfunction) and can receivestimulation signals from a neurostimulator having a pulse generator.Selective activation of a neural target which includes at least onesubset of nerves within the pudendal nerve (e.g., dorsal genital nerve,nerve to urethral sphincter, and nerve to external anal sphincter) mayalso be achieved by strategically implanting an IPC and stimulating animplanted electrode paired to the IPC using a pulse generator. The pulsegenerator may be external to the patient and provides a stimulationsignal using wired or wireless connectivity. Therapeutic stimulation canalso be provided using TENS or TMS to provide stimulation signal to anIPC from various locations such as on the posterior surface (above thegluteus maximus muscle). Potential clinical indications for thepaired-use of an IPC and stimulation electrode can include, for example,urinary retention, urinary incontinence, fecal incontinence, stressincontinence, and urinary and pelvic pain.

FIG. 10b shows example nerves innervating the lower leg and foot. Theposterior tibial nerve (PTN) descends down the posterior-medial aspectof the calf before dividing into the medial plantar nerve (MPN), lateralplanter nerve (LPN), and calcaneal nerves. The saphenous nerve (SAFN) isa cutaneous sensory nerve that branches off the femoral nerve in theupper thigh. The nerve travels down the medial-anterior aspect of theleg, provides a sensory branch to the knee and continues down the leg toprovide sensory innervation of the medial-posterior aspect of the lowerleg. Suitable implant locations for nerve cuffs, which are connected toimplanted neurostimulators or which serve as the IPCs (10 c-f) of thecurrent invention are shown proximate to individual nerves (a cuff isnot shown on the calcaneal nerve to avoid cluttering of the figure).Selective stimulation of the MPN or LPN can also be realized byimplanting IPCs adjacent to a junction where the PTN splits into the MPNand LPN. At least one stimulator 14 can be placed on the skin next toany of the IPCs in order to provide eTENS therapy. In the figure thestimulator appears just above the ankle, and is shown in an anteriorportion of the ankle, rather than posterior, to avoid cluttering of thefigure. Various anatomical landmarks may be used to assist in providingstimulation of SAFN and its branches by correctly positioning, forexample, a percutaneous needle electrode, a TENS electrode, an implantedstimulator, IPC neurostimulator. As will further be reviewed asdiscussion of FIG. 50e , in an example clinical embodiment, thestimulator is placed about 1 cm to 3 cm cephalad and about 1 cm anteriorto the medial to provide stimulation of the anterior branch of thedistal portion of the SAFN. In another embodiment the stimulator may beimplanted between the medial malleolus and the anterior tibial tendon,just lateral to the saphenous vein. Alternatively, a location cephalad(e.g., 3 or 5 cm) and more posterior to the medial malleolus andsuperficial to the PTN can be used to target the posterior branch of thedistal portion of the SAFN. In surgical procedures, the SAFN may bepharmacologically blocked near the ankle to provide anesthesia at thefoot, which suggests the location and access to this most distal part ofthe SAFN is both relatively superficial and predictable. Access toeither anterior or posterior branches of the distal portion of the SAFNare located superficial to the PTN, which is commonly 1.5 cm to 2 cmfrom the skin surface in the ankle area, and in an embodimentpositioning a stimulator 0.5 to 1.5 cm below the skin may provide asuitable target location. In some individuals, division of the distalportion of the SAFN into anterior and posterior branches at locationsgreater than 3 cm cephalad to the medial malleolus, and thus access tothese branches may vary from patient to patient. Additional locationsfor stimulation include the distal portion of the SAFN which canterminate in multiple locations: the integument proximal to the tip ofthe medial malleolus, the anterior aspect of the medial malleolus nearthe posterior edge of the greater saphenous vein, near the posterioraspect of the medial malleolus, and cutaneous areas near to hallux.Accordingly, the SAFN may be stimulated using a needle, IPC, orstimulator at a location targeted at or adjacent to the medialmalleolus. Further, multiple smaller SAFN branches may be stimulatednear the skin that they innervate. When the SAFN is stimulatedpercutaneously or cutaneously, the return electrode can be realized, forexample, as a disposable electrode attached the in step of the foot, orthe medial aspect the calcaneous on the same leg on which the SAFN isstimulated, or a site medial aspect of the knee. Ultrasound guidancecould improve success rates for correctly and easily locating the SAFN.In an embodiment, correct placement of a stimulation device targetingthe SAFN can be further confirmed by the patient's report of ‘cutaneoustingling or paresthesia’, which will be different from that evoked byPTN stimulation often perceived as sensation radiating down the foot orfoot muscle activation). In an embodiment, selective electricalactivation of the PTN or SAFN may be occur successfully when accompaniedby a perceived cutaneous sensation and reported by patients. Incontrast, PTN stimulation will typically evoke sensations radiatingalong the foot, while SAFN activation will generate cutaneous sensationson the medial surface of the lower leg. Other locations for the IPCs canalso be selected such as positioning an IPC at the level of, or below, apatient's knee in order to enhance stimulation of a nerve such as thesaphenous nerve. A number of sites and methods for stimulating variouslower limb nerves (which are suitable targets for some embodiments ofthe invention), and recording responses to the stimulation to measureneural response, are described in Chap 6, p. 125-145, ofElectrodiagnosis in Diseases of Nerve and Muscle: Principles andPractice (2013), 4^(th) Jun. Kimura (ed), Oxford University Press, whichis incorporated by reference herein.

The current clinical model of PTN stimulation for the treatment ofbladder disorders is that by providing stimulation of the PTN “trunk”,stimulation is provided to the multiple nerve branches (e.g., LPN andMPN) that converge and pass through this nerve trunk. Stimulation, suchas percutaneous stimulation, of the PTN is viewed as an efficient mannerof providing nerve stimulation in the treatment of OAB since onestimulation target can serve to stimulate multiple relevant nervepathways. The experimental results which are shown in FIGS. 13-15 werederived using a novel animal model that relies upon a continuousbladder-fill paradigm (repeated filling and voiding) that may providemore realistic results than other models of bladder function. Thismodel, results, and nerve branch stimulation paradigms of theexperiments that were done, collectively provide a new understanding ofperipheral and PTN stimulation and OAB treatment and show, for the firsttime, that selective stimulation of nerve branches can provide clinicalbenefit over full PTN trunk stimulation. For example, for a particularfrequency the stimulation of the MPN and LPN both show larger inhibitorychanges, than stimulating the entire PTN nerve trunk, in bladdercontraction activity relative to a pre-stimulation baseline level.Selective PTN nerve branch stimulation may lead to greater therapeuticeffects and fewer non-responsive patients. These findings, and theinsight provided therefrom support the design of new systems and methodsof treatment, and serve as an advantage of the current invention.

The novelty of the experimental findings presented here may be supportedin part by the difference between these results and those reported byothers (e.g., Su et al, 2013) in which the bladder was maintained at aconstant volume, whereas the model used here relies upon continuousfilling and voiding of the bladder. This difference supports the ideathat if no realistic type of voiding is provided in the animal model,then the effects of the stimulation which are evaluated at variousfrequencies may have different effects, than those shown here. The“continuous bladder-fill paradigm” used to obtain these data is novelcompared to models of the prior art and the continuous filling of thebladder can cause the stimulation protocol to produce different effectsthan what occurs with models commonly used in the prior art.Accordingly, the stimulation-related results shown in FIGS. 12 and 13-15may be absent from, in contrast with, and lead to different conclusionsabout the clinical efficacy of particular stimulation protocols,compared to results that have been found previously by others.

FIG. 11 shows stimulation targets which are spinal nerve roots thatconverge to form the pudendal (S2-S4) and posterior tibial (L4-S3)nerves. Two surgically placed IPCs (10 f-g) are indicated proximate tothe S3 and L4 roots. Electrical stimulation may occur outside the spinalcord or may be realized using a system that stimulates neural targets(for example, following a laminectomy or by surgical or percutaneousplacement of electrodes) by accessing a target through the foreman(e.g., sacral stimulation). In this example embodiment, the nerves nearthe IPCs are modulated by stimulators external to the patient such as onthe patient's skin (i.e., lower back) superficial the IPC locations.When the IPCs are implanted as part of a therapy for the treatment ofpain, then the IPCs can be implanted on, or near, one or more nerveroots (or spinal cord itself) relevant to pain signaling pathways inorder to suppress the signals related to the pain. When IPCs areimplanted as nerve cuffs that are for use with an implantedneurostimulator, the IPCs can be realized as multi-contact electrodes ofone or more leads connected to the neurostimulator 110, or electrodecontacts on the housing of the neurostimulator itself.

FIG. 12 illustrates the results of an experiment in anesthetized ratsthat indicates that direct electrical stimulation of the PTN canmodulate bladder function in a frequency-dependent manner. Theexperimental setup used to generate this data involved catheterizationof the bladder dome in urethane-anesthetized rats. The catheter isconnected, in series, to a pressure transducer and a syringe filled withsaline. An infusion pump is then used to realize a novel “continuousbladder-fill paradigm”, where repeated reflex bladder contractions areelicited (FIG. 12, top trace). The top graph shows a 10-minute train ofelectrical pulses delivered to the PTN at 5 Hz. In this example of 5 HzPTNS, a slight but noticeable reduction in the bladder contractionfrequency can be visually seen during the 10-minute stimulation trial(“acute” change relative to the pre-stimulation baseline). This isfollowed by complete inhibition of the bladder that persists beyond theend of the PTNS trial (“prolonged” post-stimulation inhibition). Incontrast, the bottom graph shows recovery of bladder activity followinga 10-minute trial of PTNS applied at 50 Hz. This particular exampleshows the abrupt transition from a flaccid (passively leaking) bladderbefore PTNS to one that generates robust sustained bladder contractionsfollowing this high-frequency PTNS. The bladder-excitatory effectremains persistent following the termination of PTNS. While the toptrace shows an example of a stimulation protocol that can be used duringtreatment to decrease bladder activity, the bottom shows how thestimulation protocol can be used to modulate the bladder to increasecontractions.

In this model, the PTN was surgically accessed and a bipolar stimulatingnerve cuff electrode was implanted directly onto the nerve. Thestimulation amplitude was set at 6 times the threshold required to evokea foot twitch (i.e., the minimum amplitude that works for thisexperimental set-up, or “6×Tm”). Although not observed in this example,this bladder-excitatory response typically occurred during stimulationand the evoked activity continued after the end of the 10-minute pulsetrain into the post-stimulation period.

FIGS. 13a, 13b, 13c , shows the summary data from a set of 11experiments that followed the same PTN stimulation protocol and“continuous bladder-fill paradigm” used in FIG. 12. There is a clearfrequency-dependent modulation of the urinary bladder in response toelectrical stimulation of the PTN trunk that is distinct compared toselective nerve branch stimulation as shown in FIG. 13a for the PTN,FIG. 13b for the medial plantar nerve (MPN), and FIG. 13c for thelateral plantar nerve (LPN). FIGS. 13a-c and FIGS. 14a-f are similar todata shown in Kovacevic M and Yoo P B, Reflex neuromodulation of bladderfunction elicited by posterior tibial nerve stimulation in anesthetizedrats. Am J Physiol Renal Physiol. 2015; 308(4):F320-9, incorporated byreference herein.

It is important to note that each stimulation frequency range canexhibit unique PTNS-evoked responses. FIG. 13a shows PTNS resulted inbladder inhibition at low frequencies, such as 5 Hz to 20 Hz; whereasbladder excitation is observed in response to stimulation at higherfrequencies such as 50 Hz. Stimulation at 5 Hz and 20 Hz elicits bothacute (labeled “Stim” in figure) and prolonged (labeled “post”)inhibition of the bladder; 10 Hz stimulation evoked primarily acutebladder inhibition with weaker prolonged inhibition; and 50 Hzstimulation elicits both acute and prolonged bladder excitation.Although using a stimulation protocol which provides at least one signalmodulated within a range of approximately 5-20 Hz as therapy for bladderdysfunction may be utilized, in an alternative embodiment thestimulation protocol can be further tailored. For example, a distinctionmay be made between acute results seen for modulation of bladderactivity which resulted during stimulation with the prolonged resultsobtained after stimulation. The acute response may be just as relevantas the post-stimulation response in the treatment of OAB. For example,when the duration of the stimulation is increased beyond the 10 minutesused here, and/or is repeated periodically or provided continuouslyduring treatment, then the acute response may dominate the therapyresponse. Additionally, when a system and method is used to provideacute modulation of a bladder condition (e.g., the detection of an eventfor which modulation is responsively provided such as patient pushing abutton on an external programmer that indicates that bladder urgencysymptoms are too severe) then the acute response may be more relevantthan the prolonged response in determining therapy parameters of thestimulation protocol. Accordingly, based on these results, in someindividuals, PTNS therapy which includes a stimulation protocol thatprovides at least one signal in either the 5 Hz or 20 Hz range for PTNstimulation may be suitable to treat idiopathic overactive bladdersymptoms. A stimulation protocol using a signal in the 10 Hz range forPTN stimulation could be suitable for the treatment of neurogenicbladder symptoms (e.g., spinal cord injury, multiple sclerosis, ordiabetes). With respect to higher stimulation frequencies, the datasuggest a stimulation protocol using a signal in the 50 Hz range (e.g.,50+/−10 Hz) for PTN stimulation could be suitable for modulating urinaryretention (related to detrusor under-activity), or bowel retention(i.e., constipation). While 50 Hz was used, higher frequency ranges suchas 100 Hz (or higher) may also result in modulation (e.g., excitation)of bladder activity.

FIG. 13b shows summary data from experiments (same setup as FIG. 12 andFIG. 13a ), where the MPN was activated by direct nerve stimulation. Inthese rat experiments, selective activation of the MPN evoked robustbladder inhibition at 5 Hz (prolonged) and 10 Hz (acute and prolonged).Although 50 Hz stimulation of the MPN failed to elicit a bladderexcitatory response as was the case for the PTN, 20 Hz stimulationappears to elicit a prolonged excitatory effect. In one embodiment, amethod using an MPN stimulation protocol having at least one frequencyselected from the range of 5-20 Hz can be used to treat OAB, whilelimiting to approximately the 5 to 10 Hz range may be preferred whenstimulation is not continuously provided, and 10 Hz may be preferredwhen stimulation occurs continuously. These data suggest that—in lieu ofstimulating the entire PTN—low frequency stimulation of the MPN is wellsuited for treating OAB symptoms. Additionally, a stimulation protocolusing 20 Hz MPN stimulation may help with treating urinary retention.The inconsistency of the excitatory response at 20 Hz suggests thatelectrical stimulation of the PTN or other PTN branches (e.g., LPN orcalcaneal nerve), at least at 20 Hz, may be a better candidate forsuccessful mediation of this bladder excitatory reflex than the MPN. Inorder to stimulate the MPN, the external stimulators, such as TENSelectrodes which provide stimulation alone or in conjunction with IPCscan be situated along the medial-plantar surface of the foot, in regionsnear the large toe, or other suitable location such as near the junctionwhere the PTN branches into the LPN and MPN or at the respective spinalnerve roots. Percutaneous, optical, (ultra) sound-based, or other typesof stimulation may also be provided using appropriately configuredstimulators.

FIG. 13c shows summary data from experiments (using same setup as FIGS.13a, 13b and FIG. 14 a,b,c) where the LPN was activated by direct nervestimulation. In these rat experiments, selective activation of the LPNevoked robust bladder inhibition at 10 Hz and 20 Hz (acute andprolonged), while 50 Hz stimulation (similar to PTN stimulation, FIG.13a ) elicits an acute and prolonged excitatory effect. This datasuggests that—in lieu of stimulating the entire PTN or the MPN—lowfrequency stimulation of the LPN (10 Hz to 20 Hz) is suitable fortreating overactive bladder symptoms, while 50 Hz MPN stimulation willhelp with treating urinary retention. In order to stimulate the LPN, inone embodiment, surface stimulation can be delivered along thelateral-plantar surface of the foot, regions near the smaller toes, orother suitable location such as near the junction where the PTN branchesinto the LPN and MPN or at the respective spinal nerve roots.

FIGS. 14a -to-14 c show the summary data (from 11 rat experiments) ofthe positive response rate of acute bladder inhibition (defined as aminimum of 10% decrease in bladder contraction rate (BCR)) that resultedduring nerve stimulation. This is expressed as the percentage ofexperiments that evoked changes in response to stimulation of the PTN,MPN, and LPN. Overall, the frequencies at which nerve stimulationresulted in statistically significant reductions in BRC FIGS. 13 a,b,cyielded response rates in the range of 50% to 67%. Interestingly, 10 HzMPN stimulation yielded an acute bladder-inhibitory response in everyexperiment, which suggests that this stimulation parameter setting couldbe used to maximize the patient response rate for treating OAB, andespecially for providing stimulation acutely to the MPN to relieve acutebladder symptoms such as urgency or incontinence. In an embodiment,percutaneous stimulation can be provided to the MPN by inserting theneedle below the medial malleolus after the junction of the PTN into theLPN/MPN. In a further embodiment, this MPN stimulation can be providedif percutaneous stimulation of the PTN is not effective. In a furtherembodiment, therapy can first be provided, for example, at 20 Hz at theconventional site for PTN stimulation and then for example at 10 Hz atthe MPN for non-responders. Alternatively, therapy can include providingstimulation at both these sites during a single treatment session inorder improve rates of patient response.

FIGS. 14d -to-14 f show the summary data (from 11 rat experiments) ofthe positive response rate of prolonged bladder inhibition (defined as aminimum of 10% decrease in BCR) that resulted following each nervestimulation trial. This was expressed as the percentage of experimentsthat evoked changes in response to stimulation of the PTN, MPN, or LPN.Overall, the frequencies at which nerve stimulation resulted instatistically significant reductions in BRC (FIGS. 13 d,e,f) yieldedresponse rates in the range of 75% to 82%. Interestingly, 10 Hz LPNstimulation yielded a prolonged bladder-inhibitory response in everyexperiment, which suggests that this stimulation parameter value couldbe used when stimulating the LPN to maximize the prolonged patientresponse rate of percutaneous or other therapy used for treating OAB,especially chronic overactive bladder symptoms.

FIG. 15 shows sample data that demonstrates the effects of saphenousnerve stimulation on ongoing bladder function. This study was performedin an anesthetized rat that utilized our “continuous bladder-fillparadigm”. A 10-minute train of electrical pulses (pulse-width=0.2 ms,frequency=5 Hz, amplitude=0.3 mA) was applied to the saphenous nerveusing a nerve cuff electrode. In this single stimulation trial, anoticeable decrease in BRC (approximately 25% decrease) was found thatwas indicative of reflexive bladder inhibition. This experimentalevidence suggests that saphenous nerve stimulation could provide atherapeutic target for treating OAB either as a single nerve target orin combination with other neural substrates (e.g., PTN, MPN, LPN,pudendal nerve), each electrically activated according to effectivestimulation parameters. The results also suggest the SAFN target canproduce bladder modulation using a stimulation signal that is 25% of theamplitude used for the PTN, MPN, and LPN sites, indicating a moresensitive bladder reflex that may be especially effective in providingtherapy, and further may be successful for patients who did not respondto other targets such as the PTN.

The experimental results which are shown in FIGS. 12-15 provide novelunderstanding of peripheral nerve stimulation for treatment of OAB. Asshown in FIG. 13 a,b,c, selective nerve stimulation can providetherapeutic advantages over full PTN trunk stimulation because, forexample, at certain frequencies the MPN and LPN both show largerpost-stimulus decrements in BCR relative to the pre-stimulus levels.Clinically, in humans, therapy using selective nerve stimulation mayalso lead to larger clinical effects of therapeutic stimulation, enablegreater time between maintenance treatments, and may lead to a decreasednumber of non-responders. Moreover, combining the data of FIG. 13 a,b,cwith the data of FIG. 14 a,b,c, further suggests that selective MPN andLPN stimulation therapy can lead, not only to larger physiologicalresponses but can also benefit a greater proportion of patients, whencompared to PTN trunk stimulation. Although the overall acute responseto 10 Hz was about −40% BRC for both PTN and MPN, selective MPNstimulation showed a 100% response rate among all 11 experiments whilePTN was below 75%, suggesting that the MPN may provide successfultherapy, or acute therapy, to a greater number of patients than PTNS.Similarly, combining the data of FIG. 13 d,e,f with the data of FIG. 14d,e,f, indicates that group mean level of the overall post-stimulation(i.e., prolonged) response to 10 Hz was about −30% BRC for both MPN andLPN during the post-stimulation period. However, when compared to MPNstimulation, selective LPN stimulation not only showed a similarresponse rate for “greater than 20% reductions” in the BRC, but it alsoshowed a minimum 10% reduction in BRC in all remaining experiments(i.e., overall 100% response rate). This suggests the LPN may be asuperior target for more prevalently providing at least a minimum levelof therapy in long-term treatment of OAB (e.g., where stimulation maynot occur chronically).

A number of additional conclusions can be drawn from combining the noveldata of FIGS. 13 a,b,c,d,e,f and 14 a,b,c,d,e,f. For example, the datasuggest that treatment protocols using PTN stimulation may provideinferior therapeutic efficacy than selective LPN or/and MPN branchstimulation as reflected in a lower total proportion of responders and asmaller physiological effect (e.g., prolonged at 10 Hz). Secondly, asystem and method of OAB treatment which uses a stimulation protocolthat combines selective stimulation of at least two of PTN, LPN, and MPNtargets may produce improved (size and prevalence of) results than usinga stimulation protocol at a single site and such a protocol is anembodiment of the invention. Thirdly, a system and method of OABtreatment which uses a stimulation protocol that combines stimulation ofat least two frequencies (e.g. alternating), applied to at least one ofPTN, LPN, and MPN targets may produce improved therapy, than usingstimulation protocols that utilize a single site and single stimulationfrequency and such a protocol is an embodiment of the invention.Additionally, treatment which uses a stimulation protocol of the PTNtrunk having a frequency such as 20 Hz, may simultaneously modulate anerve branch (e.g., MPN) in manner that contributes signals thatincrease rather than decrease in BRC (e.g., see FIG. 13b ) and decreasethe net change in BRC. In contrast, selective nerve stimulation of onlyone of the nerve branches may produce the desired decreased in BRC,without this type of unintended side-effect. These findings, as well asother insights based on these data, serve, in part, as the innovative,novel, and unobvious basis for a number of methods and systems of thecurrent invention. In relation to these results, it is interesting tonote that a common Uroplasty treatment of the PTN uses a percutaneousstimulation protocol having a signal with current level of 0.5 to 9.0 mAwhich is modulated at 20 Hz. The data of FIG. 13a suggests that 5 Hz,and possibly 10 Hz when stimulation occurs in an ongoing manner, mayprovide a larger effect of PTN stimulation in the treatment of OAB.

Assessing the data of FIG. 13a-c suggests that PTN bladder activityresponse is not the simple summation of LPN and MPN responses (e.g., 10Hz post stimulation response at PTN is smaller than that found foreither individual branch). This suggests that selective nerve branchstimulation may be better than (and/or provide different results than)stimulating the full trunk, in at least some patients. Further selectiveMPN or LPN stimulation may provide unique therapeutic outcomes. Itfollows that a patient that does not respond well to modulation of aparticular target may respond better to a different frequency or targetnerve fascicle. Nerve stimulation protocols implemented in a clinicusing external stimulation devices, or those implemented by implantableneurostimulators, can first stimulate different nerves selectively withof an individual during an assessment period and can then usestimulation protocols with site and frequency parameters that aresuccessful during treatment provision.

In an embodiment for electrically stimulating the SAFN for treatingmedical symptoms and disorders may involve the use of eTENS, where anIPC 10 f is implanted on the nerve (FIG. 10b ) near the medial malleolusand is electrically coupled with a surface electrode stimulator 14.Other possible locations for surgically implanting an IPC orneurostimulator may include subcutaneous locations at the level of (1)near the knee, (2) upper thigh, (3) pelvic area, and (4) spinal nerves(L2 to L4). The stimulation parameters (amplitude, frequency, dutycycle, etc) applied by surface electrodes at these areas may be similarto those used clinically for percutaneous PTN therapy.

Stimulating the SAFN at the level near the knee may hold advantages overstimulating near the ankle for both implantable and percutaneoustreatment. For example, some patients may have edema near the anklewhich will not extend to, or be as severe near, the knee. Further, insome subjects the distal portion of the SAFN may simply be difficult tolocalize or access near the medial malleolus. Compared to the ankle, thesize and number of axons within the SAFN branch is significantly largernear the knee and may allow for both easier stimulation and greatertherapeutic effects. With respect to implantable embodiment, the ankleregion may be found to be subject to larger movement than the tissuenear the knee leading to larger risks of migration and the patient maynot find implanted device near the ankle to be comfortable. Accordingly,due to considerations of patient comfort, clinical efficacy, ease ofidentifying and targeting the nerve, treating the SAFN near the knee mayhold advantages.

At and below the level of the knee a neurostimulator or a lead of theneurostimulator can be positioned to either stimulate the main SAFNnerve branches such as the intrapatellar branches, the SAFN branch whichcourses superficially down the anteromedial lower leg, or the cutaneousbranches that derive from the main nerve and supply the skin of theanterior thigh and anteromedial leg. While the main SAFN nerve branchjust below the knee is visible, its many smaller branches terminateacross the skin surface. In one embodiment the SAFN nerve is detectedusing imaging data or by moving to a candidate location, stimulatingcutaneously or percutaneously, and determining whether or not thesubject feels sensations in their lower leg, or both. The SAFN may thenbe stimulated to provide treatment. In an embodiment using animplantable system component such as an IPC, neurostimulator with leads,or microneurostimulator with contacts on its housing, a main branch ofthe SAFN can be surgically accessed and the relevant system component(s)implanted. Alternatively, multiple smaller SAFN branches may bestimulated near the skin that they innervate. In an embodiment, anelectrode with multiple contacts such as seen in FIG. 50a is implantedunder the skin and used to stimulate many SAFN branches that innervatethe skin. Because these may not be visible even using magnification orsonogram techniques candidate stimulations may be assessed using patientfeedback. Prior to implantation the patient may undergo an assessmentprocedure in which correct activation of the SAFN is first assessed by apercutaneous electrode stimulating at one or more candidate sites. Agrid may be drawn on the patient's leg and squares of the grid used aslandmarks. Candidate sites and depths which produced appropriateresponses (e.g., cutaneous sensation radiating towards to the ankle) canbe recorded. In the next step the surgeon then implants one or moreelectrodes or IPCs at one or more selected SAFN stimulation sites. Afteran interval during which the patient recovers, one or more stimulationprotocols can then be assessed. For example, when an electrode withmultiple contacts is used different combinations of electrodes may beassessed in order to determine which electrodes meet a criterion such ascausing cutaneous sensation. One electrode contact is then selected toprovide stimulation treatment and a second electrode contact also beselected or a portion of an implanted neurostimulator can serve as thesecond electrode. During treatment the stimulation may then be providedand the amplitude increased until sensations are felt by the patientlower in the leg. The amplitude used during subsequent treatment may beadjusted to be more than, equal to, or less then the amplitude thatproduced sensation depending factors such as patient comfort and priorresponse to therapy such as a change in baseline with respect to ameasure such as daily urinary frequency and/or urinary incontinenceepisodes following treatment. This procedure may also be used forassessment and implantation to provide treatment in the medial malleolusregion.

The appropriate placement of a neurostimulator and its electrodes can bedone using various localization methods in addition to or instead ofthose just described when larger SAFN nerve branches, rather than thencutaneous terminals, is the nerve target. In an embodiment, determiningwhere a stimulator should be implanted is to use fluoroscopy, x-ray,and/or ultrasound sonography. A stimulator can be implanted usingstandard surgical techniques or can be assisted by tools such ascustomized catheters designed to deliver a small neurostimulator totarget region. Determination of placement can also be assisted by MRIdata or a 3D model of the relevant area of a patient, and implantationcan be guided by stereotactic frame-based methods, or simply visually bythe surgeon if the implantation occurs surgically rather thanpercutaneously via a guiding catheter or enlarged needle.

In an embodiment SAFN stimulation can be provided transcutaneously usinga first surface TENS electrode placed near the knee and a returnelectrode placed, for example, at 3 finger widths below the medialcondyle of the tibia. A relatively large TENS electrode which is atleast 4 cm×8 cm may be used to minimize any discomfort and/or increasethe number of SAFN fibers terminating onto the skin surface (medialaspect of lower leg). The stimulation amplitude is then increased to anassessment threshold, for example, up to 40 mA, until sensation is feltat the location of the surface electrodes and down the lower leg. Ifthis does not occur then the TENS electrode is moved to another locationand the operation is repeated. When sensation in the leg is obtainedthen the treatment stimulation can occur for an interval such as 30-60minutes. In an embodiment, SAFN is provided as an at home supplementaltreatment by a patient every day, or less frequently, in combinationwith clinic treatments done percutaneously in order to produce anadvantage such as allowing for less frequent maintenance visits orimproved therapeutic response. Additionally, using a TENS set-up similarto that just disclosed recent data from the laboratory of Dr. Yoo hassuggested that 14 out of 15 subjects were able to detect a cutaneoussensation of tingling indicating that the SAFN was stimulatedsuccessfully by an external stimulator prior a level of stimulation thatwould cause pain to the subject. Further, in the 1 subject that did notdetect this sensation, moving the tens electrode and trying again mayhave produced positive results. These results support that TENS-basedstimulation of the SAFN between the knee and the ankle, and preferablycloser to the knee, using an amplitude of approximately between 10 mAand 50 mA. Additional therapeutic benefit may be obtained by providingthis bilaterally.

Candidate locations for implanting IPCs, implantable electrodes, and/orpulse generator device may include subcutaneous locations at the levelof (1) the ankle, (2) the knee or below the knee, (3) upper thigh, (4)pelvic area, and (5) spinal nerves (L2 to L4). The electrode stimulatorsmay be, for example, a single- or multi-contact (1) lead type electrode,(2) cuff-type electrode, (3) helical or spiral type nerve electrode, (4)injectable cylinder or pellet-type electrode, or (5) wire-typeelectrode. The electrode stimulators may receive stimulation signalsfrom an implanted pulse generator, external electrical source, TMSsource, sound source, or light source (e.g., laser) or other modality ofproviding energy.

In an embodiment a neuromodulation system for modulating a nerve targetto modulate bladder activity comprises: a) an implantable activecomponent having a receiver comprising a secondary coil, circuitry toconvert magnetic energy into electrical energy, optionally powerstorage, pulse generation circuitry, safety circuitry, and at least onestimulator having at least one electrode contact capable of stimulatingat least one spinal root nerve target of a patient selected from thegroup of L2, L3 and L4; b) an external neurostimulator comprising apower source, circuitry to emit magnetic signals, at least twopredetermined programs to control said magnetic signals, and a primarycoil that serves as a stimulator; c) the primary coil of the externalneurostimulator and the secondary coil of said implantable activecomponent being capable of forming a connection by inductive coupling,whereby said external stimulator is capable of controlling thestimulation of said at least one spinal nerve root targets which isprovided by the implantable component using a stimulation frequency andamplitude that has been shown in the patient to cause decreased bladderactivity. The external stimulator can be realized as part of an externaldevice (EXD) which is configured with a processor for receiving patientinput and controlling stimulation therapy, and the input can allow thepatient to manually start, stop, and adjust therapy provided by theimplanted active component. The EXD can be further provided with aprotocol selection mechanism having at least two predeterminedstimulation protocols that may be selectively operated, the first usinga signal that is related to long term post-stimulation modulation ofbladder activity which occurs after the stimulation has stopped and thesecond using a signal that produces relatively acute modulation ofbladder activity during stimulation

FIG. 16 shows sample embodiments of stimulation protocols for applyingelectrical pulses to target nervous tissue. An advantage of theseprotocols is supported by experimental data (e.g., FIG. 13-FIG. 14),which demonstrated reflex bladder inhibition can vary as a function ofstimulation frequency. In one embodiment, a method may utilize more thanone stimulation frequency, which has previously met some treatmentcriterion that is associated with successful patient outcome (e.g. priorsuccess in that patient or a similar patient population), in order toprovide the advantage of increasing the rate of successful patientresponse. A ‘hybrid-frequency’ stimulation method of activating nervoustissue is presented in cases I and II, where electrical pulses of thestimulation signal can be, for example, square, sinusoidal, orrectangular in waveform shape and can be applied in monophasic orbiphasic fashion. In one embodiment, the stimulation protocol for OABtreatment requires alternating two frequencies at a target site, such asproviding PTN stimulation at 5 and 10 Hz, MPN stimulation at 5 and 10Hz, and/or the LPN stimulation at 10 and 20 Hz. Two or more sites may bestimulated at a particular time or preferably the sites can bealternated. One example stimulation protocol can include three differentstimulation signals modulated at different rates (A=5 Hz, B=10 Hz andC=20 Hz) and 2 different pulse train durations (e.g., X=1 minute, andY=6 minutes). The two stimulation signals (e.g. A and B), can both occurfor a duration of X (e.g., case I), or the two (or more) stimulationsignals (e.g., B and C) can occur in an alternating manner with aduration of X and the other can occur with a duration Y (e.g., case II),which are different. For example, a clinically useful stimulationprotocol may be used if a patient can tolerate the first stimulationpattern (B) better than the second stimulation pattern (C) in which Ycan be made longer than X. Further to increase patient comfort apause-duration, during which no stimulation occurs, can be inserted intoone or more time intervals of any stimulation sequence. In addition tocomfort, another issue is effectiveness. For example, the firststimulation signal (defined by the first stimulation signal set ofparameters) may need to be provided for a longer interval than then thesignal provided by the second protocol before a desired effect occurs.Other values of the stimulation signal such as pulse width, rise time,waveshape, current and voltage level, in addition to total duration, maybe adjusted due to factors such as subjective tolerance, stimulationsite, nerve target, acute response to treatment, response to treatmentover time, or due to patient data such as patient bladder diary recordsor quality of life surveys, patient input data related to controlling oradjusting stimulation provided by an implanted device, or data sensedfrom sensors which are assessed by a doctor or by an algorithmimplemented by the treatment system.

In another exemplary method of improving PTN or MPN stimulation (caseI), the stimulation protocol is comprised of an interleaved pattern ofstimulation in which 1-minute trains of 5 Hz and 10 Hz stimulationsignal pulses are delivered throughout a single clinical treatmentsession. The total stimulation time during a treatment session may be inthe range of 30-60 minutes. In a second embodiment (case II), thestimulation protocol occurs by stimulating the LPN with a protocol thathas stimulation parameters that define a stimulation signal pattern withinterleaved pulse trains of 10 Hz for 1 minute, and 20 Hz for 6 minutes.These two example stimulation protocols may facilitate better patientresponse than using a single stimulation signal to increase therapybenefit.

These stimulation paradigms may be delivered using TENS or TMS, with orwithout an IPC, percutaneous nerve stimulation, ultrasound andlaser-based stimulation signals, and by a fully or partially external orimplanted neurostimulator. In an embodiment the implanted component mayconsist of a multi-contact nerve cuff electrode, multi-contact lead-typearray, or a multi-contact paddle-type electrode configuration.

The use of alternating stimulation protocols between two stimulationparameter sets that are designed to provide benefit can be applied tothe clinical treatment of other disorders as well. For example, thetreatment may include vagus nerve stimulation, deep brain stimulation,spinal cord stimulation, etc. The two or more alternating stimulationparameters can be adjusted for each individual patient in order toprovide improved treatment. The adjustment may be done using stimulationparameters which were derived using a calibration or testing/assessmentprocedure that occurs before (after, or during) the treatment isprovided, and which may also be carried out before each treatmentsession occurs.

In another embodiment (case III), electrical stimulation may be asinusoidal waveform that is applied to one or more cutaneous surfacesthat best activate a target such as (1) the PTN, (2) MPN, (3) LPN, (4)calcaneal nerve, and/or (5) SAFN. These areas may include the medialaspect of the lower leg, medial-posterior aspect of the lower leg,posterior surface of the foot, medial aspect of the glaborous surface ofthe foot, and the lateral aspect of the glaborous surface of the foot.The frequency of the sinusoidal signal may be tuned to, for example,2000 Hz, 250 Hz, and 5 Hz. According to Koga et al (Koga et al,Molecular Pain, 2005), these frequencies can preferentially selected toactivate Aβ, Aδ, and unmyelinated C-fibers, respectively. This suggestsan alternative embodiment using TENS/eTENS to deliver therapy for OAB inwhich, for example, a 2 kHz signal may be used to preferentiallystimulate fibers to mediate a bladder inhibitory response, especially inthe case of the superficial SAFN target.

Stimulation protocols may also use stimulation signals such asinterferential stimulation signals which may be provided by two or morestimulators to target nerves that are located near the skin surface. Inan embodiment the stimulation protocol is adopted under control of aprocessor to the geometry of the stimulators to provide summation at atarget nerve such as the SAFN. Further, the frequency or othercharacteristics of the stimulation signals may vary over time such asoccurs with a chirp-frequency modulated stimulus.

In another embodiment (case IV), both pulse-type and sinusoidalwaveforms may be combined to selectively target multiple nerve targets.With a single surface stimulator 14 placed on the medial-posteriorsurface of the lower leg (e.g., between the medial malleolus and theankle for PTN and anterior to the malleolus for SAFN) and an IPCimplanted on the PTN 10 e, a stimulating pattern of alternatingsinusoidal and pulse-type waveforms is applied. The sinusoidal waveformmay be applied at a frequency of 250 Hz to target Aδ-typefibers/receptors within the SAFN, whereas electrical pulses are appliedat 5 Hz to target the PTN. The durations of each waveform (sinusoidaland pulse-type) applied to each target may be the same or different,such as, 5 minutes and 1 minute, both 1 minute, or 1 minute and 5minutes, respectively.

FIG. 17 shows an embodiment of the invention for the treatment ofoveractive bladder or urinary retention (i.e., detrusor under-activity)that comprises a treatment method which uses an eTENS system includingthe combination of an IPC 10 e placed on the PTN trunk and a surfaceelectrode 14 placed superficial to the IPC 10 e. eTENS stimulation of apatient with an IPC placed on the PTN may be selected if an assessment48 shows that this might provide suitable therapy. The assessment 48 mayinclude using percutaneous stimulation of the PTN to determine if thisis effective in treating a patient and/or produces a desired outcome,and may occur over several weeks or months of treatment sessions. Ifstimulation of the PTN nerve trunk is deemed unsuitable as an outcome ofthe assessment (e.g., uncomfortable PTNS-evoked sensation ornon-satisfactory treatment response by the patient), then an alternativestimulation protocol can be assessed by repeating step 48. For example,stimulation of at least one of the SAFN, MPN or LPN can be assessed, andan IPC can be implanted proximate to either the SAFN, MPN or LPN if anyof these provide sufficient therapeutic benefit. FIGS. 12-14 f show datasupporting that a stimulation protocol which uses the PTN may producebetter or worse therapeutic results than stimulation of the LPN or MPN,and further, these nerve branch targets may be successful in patientswho did not respond to PTN trunk stimulation. The assessment of theSAFN, LPN or MPN can occur using a percutaneous or TENS stimulationprotocol (with or without at least one IPC) or may use light, sound,pressure, or other modality to stimulate the nerves during assessment48. Assessment may also include evaluation of acute responses while thestimulation occurs, or post-stimulation responses which may occurminutes, hours, days or weeks after stimulation. Assessment may entailevaluation of a measure (e.g. bladder activity) in absolute terms orrelative to a different period such as a subject's pre-treatmentbaseline, or in comparison to age and sex matched population normativedata. Assessment protocols can include use of bladder diaries,assessment of bladder contraction, and other patient data. Assessmentcan include filling a patient's bladder (e.g., using a transurethralcatheter) and then asking the patient to rate a measure whilestimulation is provided. For example, a visual analog scale can be usedin which the patient rates bladder comfort from 1 (most comfortable) to10 (least comfortable) or a longer term bladder diary may be assessed.The assessment protocols can also be used during the assessment of thetreatment protocol as per step 38. During assessment 38, 48 or treatment36, the placement of at least one surface stimulator 14 for thestimulation of selected SAFN or PTN nerve branches could involve theplantar surface of the foot (and/or other suitable location such astoes, lateral or dorsal foot surfaces). Assessment may also includealgorithmic (e.g., under control of a processor in a neurostimulator) ormanual evaluation of any data sensed by any external or internal sensoras described herein.

Due to the results of this assessment 38, 48 (or without suchassessment), improved therapeutic efficacy may be provided using astimulation protocol which includes the co-activation (either at thesame time or different times) of targets selected from the groupincluding the MPN, LPN, PTN, and pudendal nerve (e.g., dorsal genital)fibers, as is supported by the novel data shown in this specification.In a related embodiment, an additional stimulation may occur without anIPC, or with an IPC located in close proximity to the dorsal (clitoralor penile) nerve or the corresponding spinal roots (e.g., S3). Anothertherapeutic target involves electrical activation of the saphenousnerve. This can be stimulated directly by percutaneous stimulation,TENS, or as part of a system in which an IPC 14 is be implanted on amain SAFN nerve branch or just under the skin surface and coupled to aTENS electrode 14 or receives stimulation signals from an implantableneurostimulator. Supporting physiological data for this reflex pathwayis provided in FIG. 15. In further embodiments, specific combinations ofthe PTN, PTN branches and/or the SAFN may be implemented by surgicallyplacing individual IPCs on each neural target and selectively activatingeach nerve using target-specific stimulation parameters. In some ofthese therapeutic embodiments, at least one implantable pulse generatingdevice, may be used alone or in combination with the methods and systemsof enhanced electrical stimulation (i.e., eTENS) which may improve thetherapy of the pulse generator.

In a further embodiment, the models of FIGS. 1a and 1c , are used toselect characteristics such as the physical dimensions of, andapproximate 3 dimensional locations of, at least one stimulator and IPCas well as stimulation protocols, during the assessment 48. An exampleof such a method is shown in FIG. 17 in which at least one stimulator isselected and set up for use with an IPC 32 and then used to providestimulation to modulate tissue of the patient 8. The stimulation occursaccording to the stimulation protocol selected in step 34. Thestimulation protocol may define the stimulation parameters that are usedto create at least one stimulation signal that is applied to the nervetarget in order to modulate bladder activity. Parameters of thestimulation protocol which is defined, adjusted, or selected in step 34may include any characteristic related to the stimulation signal. Thecharacteristic may be selected from the group of: voltage, current,duration of stimulation, frequency, duty cycle, bursting pattern, burstor non-burst pulse trains, shape of the stimulation pulses or waveforms,pulse width, pulse shape, pulse amplitude, polarity, and otherparameters related to various waveform types that have been disclosed.The term stimulation frequency may also be understood to be repetitionrate. The stimulation frequencies may also denote an “average rate” atwhich electrical pulses are delivered to the nerve. In addition toapplying pulses with a constant inter-pulse interval (e.g., 20 Hz=50 msinter-pulse interval), electrical pulses may be applied in bursts orvarying duty cycles that will approximate the stated “stimulationfrequencies”. Various other parameters can be set for the stimulationsignal and these may be adjusted in any step that discloses adjusting astimulation frequency. Additionally, a stimulation protocol can be usedin which more than one frequency of stimulation is provided eithersimultaneously, sequentially, or at different times (e.g. FIG. 16). Thestimulation protocol may also be provided according to times of day,pre-programmed times, according to the preferences of the patient ordoctor, responsively according to patient symptoms, sensed patient data,or otherwise. In a preferred embodiment the stimulation is intended toproduce a desired effect which is to decrease bladder activity orotherwise treat a condition related to OAB. In one embodiment astimulation protocol can cause stimulation to occur initially in achronic, or frequent manner (e.g. 1 hour on, 1 hour off), until apatient receives sufficient therapeutic benefit. In step 34, theprotocol can then be adjusted, for example according to a treatmentschedule, in order to reduce the therapy by decreasing the duration forwhich stimulation occurs (e.g., 1 hour on, 2 hours off), or decreasingamplitude of the waveforms from a first level to a second lower level,in order to decrease side effects or energy usage of a neurostimulatorsystem (e.g., to increase battery life).

In another embodiment of the invention, at least one selected stimulator14 is used to provide a stimulation waveform to a nerve target such asthe PTN or LPN in order to augment bladder activity in a patientdesiring treatment of a condition related to detrusor underactivity(e.g., urinary retention). In a preferred embodiment the stimulation isintended to produce a desired effect which is to increase bladderpressure in a sustained manner. This may be selected to be a frequencythat has been shown to produce this effect in that patient, or is alikely candidate, such as high frequency stimulation in theapproximately 50 Hz or higher range (e.g., 40 to 200 Hz). The system andmethod can be achieved percutaneously, using a cutaneous electrodeeither with or without also implanting an IPC in order on enhancetherapy, or otherwise. If an IPC is to be used with the patient 8, thiscan occur in step 30. The stimulator may be selected in step 32, as partof a fully external, implanted or partially implanted system. Step 32can include implantation of a fully implantable stimulator andstimulation device. In step 32, the system may also be realized byselecting a stimulator which is at least one coil that provides magneticstimulation either directly to the nerve, or by way of an IPC. Inanother embodiment, an implanted stimulation device can convert amagnetic or RF field provided by an external stimulator into anelectrical field. In step 30, an IPC may be selected according to thestimulator that will be used. Stimulation can be provided for treatment,induction of treatment, treatment maintenance, in combination with othertherapy (e.g., drug), or as part of a screening test procedure. At leasta portion of the steps in FIG. 17 may be used to carry out an induction,maintenance, or screening protocol rather than an ongoing treatmentprotocol that is performed in isolation. For example, the treatmentprotocol can be done as a maintenance protocol in conjunction withperiodic percutaneous treatment (as per one embodiment of FIG. 22b ).

Different portions of the population will respond to particularstimulation parameters (e.g., stimulation frequency) better than others.The correct stimulation frequency for a patient may be derived, forexample, using a method which starts with a first protocol (a candidateprotocol selected in step 34), as shown in FIG. 17. The selected firstprotocol 34 can use an initial frequency such as 5 Hz. In the next stepof the method that frequency is used to stimulate according to atreatment protocol 36. The results can then be evaluated 38 for aselected time interval. The step of assessing the treatment protocol 38can include comparing or processing data from before, during, and/orafter the stimulation occurs and can include a single assessment periodor multiple which can span across, for example, minutes, hours, weeks ormonths. The assessment of the processed data can be done by a doctor,patient, or a device of the system such as a physician programmer 70.The assessment may be both objective, such as accomplished using analgorithm to process by a processor and evaluate sensed data, or mayutilize subjective parameters provided by the patient. Data collectedfor treatment assessment in step 38 may include storage of sensed datain a device memory, requesting that a patient input data into a systemdevice such as a computer (having a processor, and conventional computercircuitry and capacity), smartphone, or keep a diary/log, or by anyother manner of collecting data. The next step can include N iterationsof adjusting the stimulation protocol parameters 44, stimulating again36, and performing N evaluations of treatment in order to obtaintreatment test results. The treatment test results can be calculatedupon the assessment data which is collected during the assessment. Forexample, the results of the stimulation using at least 2 treatmentprotocols (as adjusted in step 44) are compared. In the case where atleast one treatment protocol produced a positive treatment result (aresult that meets a treatment criterion), then a positive treatmentresult activity can occur 40. The adjusting of stimulation protocolparameters can include iteratively selecting different stimulationsignals so that the assessment relates to different candidatestimulation frequencies, and/or candidate stimulation targets such asPTN, LPN, MPN, and SAFN (including the terminal branches that innervatethe skin).

One positive treatment result activity is that the stimulation protocolthat produced the best improvement in the patient's condition can beselected for subsequent treatment 34 and applied 36 during subsequenttreatments. Subsequent treatments may only include steps 32 to 36, orperiodically the treatment protocol can be again assessed 38 to ensurethat treatment is remaining effective. In the case of negative treatmentresult, then a negative treatment result activity can occur 42. Such anactivity is to modify treatment protocol 44 and repeat stimulation 36.Alternatively, a negative treatment result can include for example, IPCexplanting and/or implantation of an IPC in another location orimplanting an IPC with different characteristics, repositioning of anIPC, implantation of another IPC in order to attempt to improve theoutcome by adding an additional stimulation site, or other surgical ortreatment adjustment. A patient's demographics (age and gender),symptoms, and other patient data may also influence the success ofcertain stimulation protocol parameters (e.g., stimulation frequencyrange) in producing a therapeutic effect and may be used by the systemand method in order to select at least one candidate protocol 34.Stimulation parameters used for treatment, or the test protocol used todetermine at least one clinically effective stimulation parameter, canbe selected and adjusted 34 according to patient data, patientdemographics, symptoms, or other patient or disease characteristics. Themethod of FIG. 17 can be applied to AOB treatment, or any othercondition or disorder for which treatment may be sought (e.g., vagusnerve stimulation for treatment of headache).

The setting 34 and subsequent maintenance or adjustment of modulationparameters can occur similarly to the methods used in many wiredneurostimulation embodiments and according to the related methodsdisclosed herein and in the prior art cited herein. For example, in someembodiments, the processor 58 of a device used in the neurostimulationsystem may employ an iterative process in order to select modulationsignal parameters that result in a desired response which is measured orobserved in a patient. Upon determining that a modulation signal shouldbe generated, the processor 58 may cause generation of an initialmodulation control signal based on a set of predetermined parametervalues of the treatment regimen. If feedback from a feedback circuit inthe sensing or processing module indicates that a calculated measurereflects that a nerve has been suitably modulated (e.g., if an increasein a degree of coupling is observed using a correlation measure betweenmeasured activity and the stimulation signal, or a change between anon-stimulus condition to stimulus condition exceeds a threshold levelcriteria related to positive outcome 40), then processor 58 operates ina similar manner or operates according to a successful outcomeoperation. If, on the other hand, an evaluation 38 of the “feedbacksignal” suggests that the intended nerve modulation did not occur 42 asa result of the provided modulation signal or that modulation of thenerve occurred but only partially provided the desired result (e.g.,movement of a patients tongue only partially away from the patient'sairway while still allowing for unwanted blockage in a method which isused to treat apnea or aspiration), then processor 58 may change one ormore parameter values 44 associated with the modulation control signal(e.g., the amplitude, pulse duration, etc.). The steps of this methodcan occur in an open or closed loop (e.g., under the guidance of acontrol law using sensed data as input) manner, or a mixture of the twoand can also utilize one or more control laws.

In the case where tissue modulation did not produce a desired outcome,the processor 58 may modify the protocol 44, such as adjust one or moreparameters of the modulation signal periodically or otherwise until the“feedback signal” or calculated measure indicates that successfulmodulation has occurred. Further, in the case where tissue modulationoccurred, but this did not produce the desired result, the processor 58may attempt at least one other stimulation paradigm that has beendefined in the treatment regimen in order to attempt to provide adifferent outcome. If a different outcome does not occur, then a deviceof a neurostimulation system operating to perform the treatment regimenmay be configured to provide an alert warning signal a patient orphysician to this result or at least store this result in its memory. Inone embodiment this alert may indicate that a patient should move anexternal stimulator to a different location to establish the suitabilityof the pairing between a stimulator and IPC. This can serve to ensurethat there is a sufficient degree of coupling between internal andexternal system components. Based on a newly determined degree ofcoupling, the processor 58 or patient can select new parameters for thestimulation signal that is subsequently used.

In one mode of operation, which is an assessment routine (e.g., steps36, 38, 44 and/or 48), the processor 58 may be configured to sweep overa range of parameter values until desired nerve modulation is achieved.For example, the stimulus amplitude of the modulation signal may beramped up to a point which is higher than that which would be usedduring longer term stimulation therapy. This may allow a patient, or asensor which senses data from a patient, to easily measure an effectthat indicates therapeutic efficacy, such as indicating that stimulationof a target nerve is capable of producing a desired change in a patient,or indicating that the external and internal components of aneurostimulation system are correctly aligned. After the assessmentroutine has confirmed a successful system configuration, such as correctstimulator and IPC alignment, the patient can then initiate therapyusing a normal, reduced, level of the modulation signal. Alternatively,if the result does not indicate that a target level of modulationoccurred, then the system may be reconfigured, for example, a stimulatorof an external device may be moved and the assessment repeated.Assessment routines may occur over extended periods such as multipledays and can utilize temporary system components such as temporary leadsor IPCs.

The stimulation provided to the nerve targets shown in FIGS. 10 and 11,or other targets stimulated during treatment, may occur using a systemconfigured for using cutaneous electrodes to provide transcutaneouselectrical pulses to a nerve or to nerve+IPC surgically placed on,around, or near the intended nerve target(s). Stimulation may also beprovided by systems and methods designed to deliver electrical pulsesusing one or more of, for example, percutaneous electrode stimulators,cutaneous electrodes, implanted electrodes, implanted stimulationdevices powered by magnetic or RF means, implanted electrodes powered byelectrical means, and implanted electrodes powered by an implantablepulse generator. Further, the nerves may be modulated by electrical,magnetic and/or chemical means (e.g., as part of step 40). Drugs may beprovided by injection, orally, or otherwise, prior to, during, or after,electrical nerve modulation during treatment as part of the treatment.Nerve activity may also be modulated by surgical, pressure, optical(e.g., laser stimulation), (ultra-)sound, genetic, or other means ofinfluencing nerve activity during therapy. The stimulation can beprovided chronically, acutely, periodically, or responsively by adoctor, patient, or device having sensing capability. For example,stimulation could be provided for 15 minutes each day, or may beprovided in response to bladder pressure which is sensed by a sensorimplanted or eternal to the patient. Stimulation can be provided that isresponsive to patient's needs. For example, a patient may use anexternal device to communicate with an implantable device and cause itto operate to provide stimulation for a given duration starting 40minutes after eating lunch, or in response to a button press, forexample in order to cause urination to occur (due to the provision ofnerve modulation that produces bladder excitation) while the patient isin the lavatory.

Therapy for overactive bladder and related disorders can be providedresponsively 36 to user input such as a button press on the EXD 72 whichis communicated to the processor of a neurostimulator, or may bedetected by an implanted stimulator in response to sensed data from apatient, in response to sensed pressure, flow, motion, position or otherdata, or in response to time data such as clock time or a time intervalsuch as time since last voiding. OAB may be particularly problematicwhen the patient is sleeping and so therapy can be delivered during thattime. Providing therapy to a sleeping patient may allow the patient toexperience fewer side effects, such as unwanted tingling. The therapyprotocol may trigger a stimulation protocol to begin in response to apatient input (provided when the patient is going to sleep) and maydictate that stimulation should start 1 hour after sleep onset and lastfor a duration such as 3 hours. The occurrence of sleep may also bedetected in response to evaluation of time data (e.g. 12 a.m.), senseddata, motion data, etc indicating, for example, that the patient islaying down and not active.

Treatment of Incontinence Related Disorders Using Pudendal NerveCo-Activation

Some studies in anesthetized rats have only demonstrated reflexivebladder inhibition during PTN stimulation while failing to showexcitatory effects (e.g., Su et al., Am J Physiol Ren Physiol 2012, Suet al., NAU 2013). These prior studies found that only 10 Hz PTNS waseffective at inhibiting the bladder in rats. A difference between theexperimental setups of this prior art and that used to derive theresults disclosed herein is the provision of continuous urodynamicbladder filling (“Continuous bladder-fill”). The prior art studies usedan isovolumetric bladder model in which there is no fluid flow throughthe urethra during bladder contractions. In contrast, the continuousfill model used to generate the data of FIGS. 13-15, and elsewhere,shows that these unexpected bladder reflexes (both inhibitory andexcitatory) are produced, or unmasked, when both the PTN and pudendalnerve (urethral) afferents are simultaneously activated. A method ofusing this model to derive candidate stimulation parameters fortreatment using simultaneous stimulation of two nerves is an aspect ofthe current invention.

Although the influence of PTN (Su et al., Am J Physiol Ren Physiol,2012; Su et al., NAU 2013) and pudendal nerve (Peng et al., Am J PhysiolReg Int and Comp Physiol, 2008) afferents on bladder function has beenshown individually, the combined effects of activating both pathways hasnot previously been demonstrated since the prior models do not providefor combined activation. The combined activation is likely more thanjust the sum of the multiple reflex pathways because the effects ofstimulation, as well as stimulation at particular frequencies, usingonly 1 nerve may be different than the case where other nerves are alsoactivated. The novel model disclosed here, combined with the lack ofsuccess of other prior art models to yield similar data, allowed thediscovery of this relationship which serves as the basis for someembodiments of the disclosed invention. The simultaneous stimulation hasbeen shown to produce clinically effective stimulation in a model wherethe bladder is modulated by a first stimulation site (e.g, pudendal,sacral, and/or pelvic nerve) when this occurs with co-activation ofstimulation of a second site (e.g., PTN or MPN or LPN). Further, byremoving the modulation of the bladder by the first site, thestimulation at the second site can become much less effective producing,or at least demonstrating bladder modulation in response to stimulation.These findings support the novel approach of modulating bladder functionby co-activating SAFN, PTN, LPN, and/or MPN as well as the pudendalnerve afferents in a patient suffering from a urological disorder.Accordingly, in one embodiment of the method shown in FIG. 17, at leastone of the steps 30-36 can be adopted so that both the pudendal (orsacral or pelvic) nerve and at least one of the PTN, a PTN nerve branch,or SAFN (or branch) are both stimulated. A stimulation protocol of atleast one neurostimulator which is configured to provide stimulationsignals to stimulators configured to stimulate these two targets, may beconfigured to provide co-activation, for example, at the same time or inan interspersed manner. Further, the combinations include stimulation ofthe nerve root spinal sites related to the PTN, SAFN, or their branchesmay serve as surrogate.

In one embodiment, shown in FIG. 10a-b electrodes or IPCs are implantedaround, or in close proximity to, target sites on nerves in the regionof the foot as well as on or near 1) the pudendal nerve, either theurethral sensory or the dorsal genital nerve, 2) the PTN, and 3) theSAFN. In an embodiment, up to three independent stimulation sources maybe used to deliver electrical stimulation to these target nerves.Further, in embodiments at least three IPCs 10 or leads may besurgically placed on or around spinal nerve roots that best representthe sensory afferents of the pudendal, PTN, LPN, MPN and SAFN asillustrated in FIGS. 10a-b and 11. In one aspect of this latterembodiment, surface electrodes could be applied on the lower back, andmore specifically may correspond approximately to the locations of thesacral and lumbar nerves. Stimulation can be provided by externalstimulators and IPCs 10 and/or at least one neurostimulator having atleast one implanted component. Transcutaneous pulses can be delivered bytwo or more electrodes or a surface array of multiple-contact electrodes(e.g., two or more electrodes can be placed on the patient's back usingthe system of FIG. 18a ), in which specific contact(s) of an electrodegrid array can be used to selectively activate targeted spinal rootswith the use of IPCs.

In addition to stimulating the entire pudendal nerve at a particularstimulation site, the coactive stimulation provided by the stimulationprotocol may be applied to the any of the particular branch of thepudendal nerve (e.g., dorsal genital nerve or urethral sensory nerves),or to the pelvic nerve branches (e.g., bladder neck sensory nerve).Further, the co-active stimulation parameters for the nerve branches maybe the same, or different, as those used for the full pudendal nerve.The timing of electrical stimulation of both pathways (e.g., PTN andpudendal) may be applied in a synchronous or asynchronous manner.

Therapeutic electrical stimulation for OAB can be applied in varyingdoses according to the stimulation protocol (e.g., duration=5 minutes to1 hour) and intervals (e.g., daily, twice-daily, or weekly) that bothmaximize therapeutic efficacy and/or patient comfort. For the treatmentof urinary retention, electrical stimulation may be applied up to apre-voiding time such as 30-minutes before and during the “anticipatedtime” to empty the bladder. Further, a sensor, such as an implantedsensor for measuring patient data related to bladder volume couldfacilitate stimulation timing. A stimulation system having at least oneimplanted component and having sensing module 55 for obtaining andevaluating sensed data in order to provide feedback or closed loopcontrol of therapy by a stimulation module 54 would be one suitablecandidate system. A sensor 634 may be used to provide sensed data to animplantable neurostimulator which could process the data and then, ifmerited, communicate this data to an external patient device which, inturn, could provide visual, auditory, or other signal to a patientsignaling that voiding is warranted. A patient can operate a externaldevice to cause the implantable neurostimulator to stop/startneurostimulation to modulate activity such as to provide therapeuticbladder inhibition.

Based on the results of FIGS. 13-15, a further embodiment of treatmentfor bladder disorders may involve a stimulation protocol involvingstimulation 626 of at least one PTN and/or SAFN branch and concomitantactivation of the pudendal nerve (dorsal genital or urethral sensory).The ability to activate these excitatory and inhibitory bladder reflexesby selective PTN branch stimulation suggests that systems usingcombination stimulation of neural pathways can be utilized for improvingtherapy for bladder disorders.

Based on the results of FIGS. 13-15, a further alternative embodiment oftreatment for OAB involves providing a first stimulation signal, forexample, in the 5 Hz range for the PTN, MPN, and/or SAFN and providing asecond stimulation signal to provide simultaneous pudendal nervestimulation. The second stimulation signal can be in a range from, forexample, 5 Hz to 20 Hz, or 2 Hz to 50 Hz. The second stimulation signalcan alternatively, or additionally, be used to stimulate a nerve targetwhich is the sacral nerve and/or pelvic nerve (e.g., via S3).

Based on the results of FIGS. 13-15, a further embodiment of a systemand method for treatment of OAB may involve providing a stimulationsignal, for example, 10 Hz stimulation of at least a first nerve targetincluding the PTN or SAPH branch. A second stimulation signal can alsobe used to provide co-activation of the pudendal, sacral, and/or pelvicnerve stimulation. The second stimulation signal can occur, for example,at 1 Hz to 100 Hz, and preferably between 2 Hz to 50 Hz.

A further embodiment of OAB treatment involves providing a firststimulation signal of approximately 20 Hz to at least a first nervetarget which is the PTN, LPN or SAFN. A second stimulation signal canprovide approximately simultaneous co-activation of the pudendal nerveusing, for example, at approximately 2 Hz to 25 Hz.

A further embodiment of treatment for OAB involves providing a firststimulation signal of for example, approximately 50 Hz to a first nervetarget which is the PTN or LPN. A second stimulation signal can provideco-activation of a second nerve target which is the pudendal nervestimulation, for example, at approximately 2 Hz to 50 Hz. Thisembodiment can be used to increase the bladder activity of a patient.

In another embodiment, a first nerve target (e.g., the PTN or MPN) isprovided with stimulation that occurs periodically while simulation of asecond nerve target (e.g., S3) is chronically provided such as by animplanted neurostimulator in order to provide better treatment than thelatter alone due to different mechanisms of the two targets. Variousstimulation protocols may be designed so that stimulation at the firstand second nerve targets occurs at different or overlapping times.However, as has been disclosed, approximately simultaneous co-activationby stimulation of the second site may augment the influence thatstimulation at the first site has in modulating bladder activity. Inembodiments, the stimulation parameters for the first site and secondsite, can include stimulation parameters for the second site which arebased upon the data of FIGS. 13-15 and selecting those frequencies whichwere found to provide larger modulation. Alternatively, differentstimulation parameters can be used.

Increased Therapeutic Benefits

Based on the results of FIGS. 13-15, novel systems and methods ofselectively stimulating the various PTN nerve branches may offerimproved therapy. For example, in an embodiment a stimulating electrodethat targets the tissue of, or proximate to, the large toe (with areturn electrode located on the medial surface of the foot, orelsewhere) can selectively activate the MPN. An electrode can be locatedto provide stimulation to a target near the three smaller toes toactivate the LPN (with a return electrode located on the lateral surfaceof the foot, or elsewhere). The stimulators may be applied and held inplace using conductive electrode cream as is often done with TENS, maybe held at appropriate locations by an elastic band, disposableelectrode, or sock. In order to increase the responsiveness of thenerves to stimulation, IPCs can be implanted in the foot to activate thetarget nerve. The IPCs can also be implanted below the medial malleolusafter the bifurcation of the PTN to enable selective stimulation of theMPN or LPN.

The limited efficacy of PTN stimulation near the medial malleolus serveto highlight some selective PTN branch stimulation benefits. During PTNstimulation other nerves that converge in the PTN, such as the calcanealnerve, may be electrically activated and cause great discomfort to apatient. The unwanted activation of such non-targeted nerve fibers canlimit the total amplitude of the stimulation signal and thereby limitthe sufficient recruitment of targeted fibers needed for suppressingbladder symptoms. Even at larger amplitudes, PTN modulation of bladderactivity can be less than that enabled by selective nerve branchstimulation. Su et al (Am J Physiol Ren Physiol 2012) showed an upperlimit of stimulation amplitude (4×Tm in rats), beyond which PTNS failsto suppress bladder activity. Selective nerve branch stimulation mayenable TENS therapy to occur either at home or in the clinic, ratherthan requiring percutaneous stimulation to provide sufficient energy tomodulate bladder activity.

Electrically stimulating more than one PTN nerve branch, as occurs withPTN trunk stimulation, may cause certain nerve fibers to produce smalleffects, no effect, uncomfortable/painful side-effects, or effectsopposite to that of the intended modulation of bladder activity. Forexample, electrical stimulation of the entire PTN at 5 Hz producespost-stimulation inhibition which is similar to that seen whenstimulating only the MPN (FIGS. 13, 14 b) while having little or even anopposite effect via stimulation of the LPN. Selectively activating aspecific nerve branch, instead of the entire PTN, may provide advantagessuch as less side effects, increasing the number of recruited nervefibers, and greater treatment efficacy.

At higher stimulation frequencies, selective PTN branch stimulation mayprovide an effective means of generating or increasing bladdercontractions and thus improving voiding efficiency. The inability toempty the bladder is characteristic of what is called urinary retention,where among myriad factors the underlying pathology may involve detrusorunderactivity. As an example, stimulation of the PTN at 50 Hz producedabout a 30% increase in BRC as a % of control (pre-stimulation) whilestimulation of LPN produced a 130% increase (the response in FIG. 13Cextends far beyond the top of the graph). In contrast, MPN stimulationgenerally produces a decrease, rather than increase, in bladder activityat this higher stimulation frequency. These data suggest that bladderexcitation by stimulation of the whole PTN is partially retarded byco-activation of the MPN (although the PTN response is not the simplenet effect of modulation of PTN and LPN). As such, a system and methodwhich uses a stimulator for providing at least one stimulation signal inselective activation of the LPN may improve the treatment of detrusorunderactivity compared to PTN. Selective stimulation of individual PTNbranches may be accomplished using percutaneous, TENS, eTENS, magneticand other stimulation methods as are disclosed herein. Further, bothassessment and stimulation protocols can stimulate the LPN, MPN, and PTN(as well as other peripheral nerves such as the SAFN) to uniquelyproduce different amounts of bladder excitation or inhibition. If aparticular frequency and/or nerve target combination does not providethe desired modulation or therapeutic effect during either assessment orprovision of therapy, then an alternative combination could be attemptedsince it may provide improved therapy. Stimulation parameters and sitesthat provide improved modulation can be stored (e.g., as part of step630) and subsequently used during by the stimulation protocol usedduring therapy 626.

The data presented in FIGS. 13-15 suggest that selective PTN branchstimulation may provide a means of increasing the 60% to 70% of patientswho respond to PTN stimulation therapy, and improving the extent towhich unwanted bladder symptoms are suppressed and abnormal bladderactivity is treated. Selective PTN branch stimulation can activate onenerve using a selected amplitude and frequency or can be applied tomultiple nerve branches, either simultaneously or in an alternatingfashion. These experimental results were obtained using pulses appliedat 6 times the threshold for motor movement of the foot in anesthetizedrats. Although this is significantly higher than what is used in humans(typically the threshold for foot twitch), anesthesia effects may bepartially responsible for such high stimulation amplitudes. The benefitsof different stimulation sites and signal characteristics used in humansmay depend on the maximum amplitude tolerated by individual patients.

Induction and Maintenance Therapy for OAB

FIG. 22c shows an embodiment of the current invention as a method oftreating OAB comprising combining a first step of providing a firsttreatment protocol 252 such as stimulating the PTN percutaneously duringa first treatment interval, which may occur inside or outside of aclinic, and the second step of providing a second treatment protocol256, during at least one second treatment interval, such as anadditional therapy that may include at least one of selective PTN branchstimulation including, for example, LPN and MPN stimulation. The therapyprovided during the second treatment protocol 256 is realized usingeither transcutaneous or percutaneous stimulation, and which may use anIPC to improve stimulation. The second treatment protocol 256 can beprovided at approximately the same time or within the same treatmentsession as the primary treatment protocol 252 (e.g., percutaneousstimulation in the clinic). Alternatively, the second treatment protocol256 can be provided between first treatment protocol treatments of thefirst therapy 252 in order to improve the therapy (e.g., clinicallybased percutaneous treatment sessions in a clinic as may occur duringtherapy induction) or as maintenance therapy. The additional therapyprovided by the secondary treatment protocol 256 can be provided usingan external device configured to provide different types of stimulationsignals (e.g., a TENS device, in the patients home). The provision ofsecondary therapy 256 can also be provided by stimulation signals andmodalities such as RF, light/laser, sound/ultrasound, or other modes ofstimulation that use various technologies as are disclosed herein. Theprovision of secondary therapy 256 can be implemented using an IPC whichis used in conjunction with an external stimulator to provide anelectrical, ultrasound, or laser stimulation signal other type ofenhanced nerve stimulation, as disclosed herein. The secondary therapy256 can comprise a secondary stimulation protocol that stimulatescutaneously located nerve branches (e.g. SAFN) while the first therapyprotocol provides a first therapy that stimulates deeper nerves (e.g.PTN). In addition to providing the first and second stimulationtreatments, in an alternative embodiment, the effects of thesetreatments can be assessed 254, 258 and used to adjust at least one ofthe treatment protocols. For example, if therapy does not meet at leastone therapy criterion then a treatment such as the second treatment canbe adjusted by changing the stimulation protocol according to at leastone of the following: changing from LPN to MPN stimulation, changingfrom MPN to LPN stimulation, and changing a characteristic of thestimulation signal that is used. Alternatively, the patient response tothe first stimulation protocol can be used to adjust the secondstimulation protocol 256 (arrow E). For example, if percutaneoustreatment of the PTN is found to produce a large therapeutic response ata particular frequency, then that same frequency can be used in theselective nerve branch stimulation. Alternatively a different frequencyrange can be assessed and selected for the secondary stimulationprotocol. As shown in FIG. 22c (arrows C and D) the primary andsecondary treatment protocol may simply be provided in an interleavedfashion. When the secondary treatment protocol 256 is home based, it maybe repeated several times before the first (clinic based) protocol 252is again repeated. In this manner, eTENS home based therapy may be usedto extend the durations between which clinic-based percutaneous therapyoccur. The secondary treatment protocol can be provided by the patientone or more times each day, one or more times each week, or asinfrequently as one or more times each month, depending upon the patientresponse to treatment. Regardless of whether the secondary treatmentprotocol is provided in a clinic or at home, this may occur duringstimulation sessions of 30 to 90 minutes. The protocols which define theprovision of the first and second treatments 252,256 may define, forexample, duration of treatment, inter-treatment intervals, and thestimulation signal, target nerves, and method of providing stimulationto a target nerve. These stimulation parameters can be adjustedaccording to the patient or doctor based upon an assessment of thepatient response. The assessment of the patient response to treatmentwhich occurs in steps 254, 258, and 260 can include assessment ofpatient data, and can be used to adjust the stimulation treatmentprotocols in various manners. For example, assessment of the patientresponse can lead to increasing or decreasing the interval betweenstimulation treatment, changing stimulation parameter such as thoserelated to waveform, current, voltage, stimulation site, and duration ofeach treatment.

Additional Embodiments for Therapy for OAB

In an embodiment, a method and system for improving nerve stimulationtreatment efficacy in a refractory patient, who has been assessed 254 asnot responding sufficiently to a first treatment protocol which is PTNtreatment, comprises administering a second treatment protocol 256 whichis a combination therapy. The therapy can combine stimulation of the PTNwith stimulation of one of the LPN or MPN (or LPN can be combined withMPN). The stimulation is at least one of transcutaneous, with or withoutan IPC, percutaneous, or may be provided by at least one implantedneurostimulator device having a pulse generator. Because the LPN and MPNcan provide different efficacy than PTN stimulation, the combinationtherapy stimulation may produce larger and more consistent results thanany of these alone. The therapy may also be applied to a patient who isnot refractory. Combination therapy may occur at the same time, atdifferent times (to avoid interaction effects), and may occurunilaterally, or one stimulation signal can be applied to the left sideof body while the other is applied to the right (i.e. bilateralstimulation). When this therapy is accomplished by one device 50, thedevice should be provided with a signal generator configured to provideat least two independent stimulation signals to stimulate two therapytargets of a patient and to implement either monopolar or bipolartherapy at each site. A signal generator module 62 may contain two pulsegenerators, each of which is configured to provide selected stimulationprotocol which is applied to a nerve stimulated by a stimulator of thedevice 50, according to combination therapy defined in a therapyprotocol.

Because combination treatment does not allow assessment of theindividual treatments, a system and method of treating a patient withbladder dysfunction can comprise treatment with a first stimulationprotocol to the PTN for a first period 252, and then if assessment ofresponse to the stimulation 254 indicates the stimulation is noteffective, an alternative second treatment protocol is selected 256 toprovide at least one of the LPN or MPN. Alternatively, treatment of theLPN, can be followed by a second protocol stimulating PTN or MPN.

Systems and Methods for Providing Nerve Stimulation

FIG. 18a shows a nerve stimulation device 50 that can be used to realizethe methods and systems of the current invention. The device 50 isillustrated with a number of modules and components which may beincluded or adjusted in various embodiments. The device 50 comprises acontrol module 52 having a processor and control circuitry forcontrolling the various other modules such as the stimulation module 54and sensing module 55 according to user input and/or treatment protocolsand parameters stored in the protocols and parameters module 66.Treatment protocols can include stimulation protocols, sensingprotocols, and evaluation protocols. These protocols may enable thedevice 50 to responsively adjust its operation in relation to theevaluation of sensed data, detection of events, patient input, timeintervals, and other triggers that can cause the selection, provision,and adjustment of therapy. The device 50 can also simply providestimulation continuously. The control module 52 has a timing module 56including a real time clock and a timer, a processing module 58including at least one processor for operating software, and processinginformation and parameter settings that are stored in memory module 60and which allow for control of device 50 operation. The stimulationmodule 54 can control at least one waveform generator/signal processorsuch as module 62 that contains circuitry for generating pulses orarbitrary waveforms for output including alternating current (AC) and/ordirect current (DC) signals to be used by one or more electrical,magnetic, optical, sonic, ultrasonic or other types of stimulators. Thesensing module 55 (shown in FIG. 18b ), may be realized as part of theAD/DA module 64 when AD/DA circuitry allows for both signal generationand acquisition, and contains circuitry and protocols for conditioningand analyzing sensed data and can also for providing power to, and/orcommunicating with, sensors. The processing module 58 enables theassessment of sensed data and can provide detection of events that aredefined to cause delivery or adjustment of stimulation. This may occurin a closed loop manner, or may cause information (information about thesensed data) or signals (a flashing light) to be presented to a user ofthe device 50, such as by an external patient device 72 or physicianprogrammer 70, who may then provide or adjust therapy. The processingmodule can aid in, for example, processing data as part of steps such as38, 40, 42, and 258. For example, sensed data can be compared to atleast one treatment criterion, and if the criterion is passed thenstimulation is not changed (or is not provided), and if the treatmentcriterion is not passed, then stimulation is adjusted or provided, asdefined by the treatment protocol. The processing module 58 may beconfigured to store a historical data record in order to track patientdata, and usage and compliance data which may be especially helpful inallowing a doctor or patient to assess compliance when the patient usesthe system at home. An AD/DA module 64 allows for conversion of inputand output signals as well as amplification, digital signal processing,filtering, conditioning, and also contains safety circuitry to ensurepatient safety. The AD/DA module 64 may also contain circuitry formultiplexing signals across different sensors or stimulators. Theapparatus 50 also includes a communication module 68 for providing wiredand/or wireless communication with other devices (e.g. an IPC which hascommunication circuitry and/or RFID identification means to communicatewith the device 50, a physician programmer 70 or patient external device(EXD) 72. The communication module 68 can communicate with a computer atremote medical facility (which may serve as a second type of physicianprogrammer 70′ that allows device communication and programming to occurremotely) either directly, via the EXD 72, Bluetooth, or WiFiconnection. The communication module can provide signals to transceiverswhich provide one way or two way communication of wireless power and/ordata signals to implantable components such as neurostimulators. Allwired or wireless communication can be realized at least partially usingthe internet, a local area network, and may also include means formagnetic, radiofrequency (RF), optical, sonic, and/or other modes ofdata and power communication with other devices. The communicationmodule 68 and/or EXD 72 may include circuitry and routines forestablishing WiFi, Bluetooth, cellular, magnetic, magnetic inductance,microwave, RF, electrical, optical, sonic, RFID, or other types ofcommunication using communication/interface ports 82 which may controlrelated devices. The communication module 68 is configured for use withUSB connectors and the like. The communication module 68 of the device50, as well as communication circuitry which may be provided on astimulator 14 and/or IPC 10 may operate to send or receive signals usingnear field, far field, induction, magnetic resonant inductioncomponents, coils, antennae, and/or rectennae, optical sensors andstimulators, sonic stimulators and sensors, etc. This allows forsuccessful communication of identification, data or power signalsbetween any external and internal components of a particular embodimentof the invention. The apparatus 50 also has a power supply module 74which can include components such as a battery, AC and DC converters,diodes that function to rectify wireless power signals harnessed byrectennae and circuitry related to the conversion or provision of powerwhich may be related to harvesting or transmission of wireless signals,and can provide a power cord for connecting to a wired power sourcethrough at least one of the communication/interface ports 82. In anembodiment, a processor of the simulator that provides simulationrelated to therapy resides within the physician programmer 70 which maybe realized as a laptop computer that can calculate and provide themodel result data. These data may be used by a physician, and can beused by control circuitry of a neurostimulation system, to adjust andcontrol the stimulation circuitry in order to provide stimulation to thepatient according to a stimulation protocol. In an embodiment thecomputer module performing the simulation is adjusted based upon imagingdata scanned from a patient, such as collected MRI or sonography inorder to reflect the physical characteristics of an area of a patient'sbody within which the stimulation target is located. The activation andcontrol of the stimulation grid array 100 may occur according to resultsprovided by the simulation in order to increase the probability that theIPC will successfully serve to enhance the stimulation of target tissue.

The communication module 68 can work in conjunction with the userinterface module 76 which contains hardware and software for presentinginformation to a user (e.g. patient or physician) and obtaininginformation/input from the user. Although the device 50 may communicatewith a physician or patient programmer 70,72, such as may be realized bya specialized device, smartphone or tablet computer, the device 50 mayalso have at least one signaling module 78 with related circuitry andcontrol a display 79 for presenting visual data in both text andgraphical format, and for presenting alarms which are related to theprovision of therapy and contain a speaker for presenting auditorysignals. The signaling module 78 can have a Bluetooth enabled soundsystem that communicates with a speaker, or sound transducer such as ahearing aid by way of the communication module 68. The device 50 canalso contain patient interface module 80 with controls such as akeyboard, nobs, switches, etc. to allow a user to provide input, such asthrough a menu guided system, as well as adjust operation of the deviceby manually adjusting nobs related to the operation of the device. It isobvious that various modules such as modules 78, 79, and 80 can also berealized within the physician or patient programmer 70,72.

Both the control module 52 and the waveform generator module 62 may beconfigured with safety hardware and software routines, includingcalibration routines to calibrate the apparatus 50 and to ensure properfunctioning. In some embodiments, the control module 52 allowsstimulation programs to be implemented according to protocols stored inthe device memory and according parameters that can be adjusted by auser's manual input obtained by the patient interface module 80, but thesafety routines may limit the adjustments to be safe.

The device 50 may use at least a first stimulator conduit 84, a secondstimulator conduit 86, to communicate signals to a first stimulator 88and second stimulator 90. In an embodiment, conduits comprise single ormulti-stranded electrically conductive, insulated electrode lead wiresand stimulators may be electrically conductive cutaneous electrodes. Thefirst conduit 84 has a first end connector 92 that may contain a plugthat electrically couples to a first stimulator interface port 83 a ofthe interface 82. The first stimulator 88 is preferably secured to thesecond end connector 94 of the stimulator conduit 84 using a stimulatorconnector 89 a. The stimulator connector 89 a may be an adaptor such asa metallic snap that is configured to connect with the second endconnector 94 a.

The second conduit 86 also has a first end connector 92 b and a secondend connector 94 b. The first end connector 92 b of the second conduit86 electrically couples to a second stimulator interface port 83 b. Thesecond stimulator 90 can be connected to the first end connector 94 b ofthe second conduit 86 using an electrically conductive connector 89 b.The second stimulator interface port 83 b may be connected to a TMSdevice to control the provision of magnetic stimulation as part of thesystem and method of the current invention.

Additional wire interface port 83 c is shown that allows for anotherstimulator to be used. Additionally, rather than stimulators, theinterface ports 83 can be connected to sensors. Further, when thestimulators are, for example, cutaneous electrodes, then the electrodecan serve as both stimulator and sensor at different moments in time. Inother words a stimulation electrode 88 can serve as sensor when thesensing module rather than stimulation module is operational for aspecific port during a period when sensing occurs.

The interface ports 83 a-c may each be configured to connect to conduitshaving a plurality of wires. S stimulator connectors 89 configured onthe stimulators can be configured to receive multiple conduit endconnectors. For example, a conduit 84 may be realized as a ribbon cablethat terminates in an end connector 94 a having multiple contactsconfigured to attach to at least one stimulator end connector 89 andwith the other end 92 a configured to be plugged into an interface port83 which is configured to operate multiple contacts related to thechannels of the conduit 84. Accordingly, in an embodiment rather thanhaving a single conductive surface of one polarity, a stimulator may berealized as at least one bipolar electrode having a first contact 96,and a second contact 98, connected to circuitry of the device by twostimulator connectors 89 (not shown) that are configured to attach to atleast one end connector 94 a of a conduit 84, and which may be separatedby non-conductive surface 97. In an embodiment the bipolar electrodecomponents including the contacts 96,98 and the non-conductive surface97 that has been paired with the IPC length. The contacts 96, 98 mayserve as an anode and cathode respectively or may both be anode orcathode with another electrode, located elsewhere, serving to completethe circuit. In a preferred embodiment the non-conductive surface wouldhave a width that was the same width “W” as that of an IPC of thecurrent invention. In an embodiment, the non-conductive surface may betransparent so that a user can see the IPC under the skin or a markingon the surface of the skin in order to aid alignment during affixationof the stimulator to the patient. Further, a stimulator can beconfigured as an electrode grid or multi-electrode array 100 havingmultiple contacts arranged in a grid pattern or otherwise, each of whichis configured to communicate with a unique contact of a connector 89 andthen channel of a conduit 84 so as to be individually operable duringstimulation. In an embodiment used on the skin surface, unlike a “Utah”array which typically uses needle electrodes to stimulate nerves invivo, the contacts may reside on a flexible or rigid substrate and beabout 1 cm by 1 cm, with 0.5 cm of non-conductive material distancebetween the individual contacts can be routed using individual wires toan interface having multiple contacts which communicates with the device50. Alternatively the individual contacts of a grid can be activated bysignal routing/multiplexer circuitry incorporated in the grid array toroute the electrical signals to the appropriate electrode contacts, forexample, under control of the processor 52. In an embodiment, individualelectrode contacts of the electrode array 100 may be used toelectrically stimulate the patient, and improve alignment with an IPC ortarget nerve, using signal routing and control circuitry in thestimulation module 54 of the device 50 to provide for spatial ortemporospatial defined stimulation patterns. The grid array stimulator100 may contain a signal router in order to cause spatial, orspatial-temporal patterns to be implemented using contacts of the gridarray, under the control of the stimulation module 54, or the moduleitself may contain the multiplexor. The electrode grid 100 may alsoincorporate optical elements, such as LEDs, which can assist withvisualizing a shape of the active grid elements and aligning an activeelectrode grid area with an area of skin 20 of a patient 8 or with animplanted IPC. The interface ports 83 may also connect in a wired orwireless manner to communicate with and/or power various sensors, suchas sensors that are configured to measure bladder activity, bladderpressure, bladder fullness, or other characteristic related to acondition or disorder being treated. Additional sensors and stimulatorsare not shown in addition to sensor/stimulator electrodes 88,89 to avoidcluttering of the figure. A treatment protocol can be stored in theprotocols and parameters module 66 which causes the grid array toprovide stimulation using 2 or more unique row activations in a mannerthat assists with aligning the active element of the grid with an edgeof the IPC. For example, the grid array stimulator 100 may have a gridof 10 rows of contacts and 12 columns of contacts. One stimulationprotocol can have a first step where a stimulation signal is provided byall the elements of rows 1 and 10, a second step where a stimulationsignal is provided by rows 4, and 10, and a third where stimulation isprovided by rows 8 and 10. In each step, unique row activation isprovided for 1 minute, and within a 30 minute stimulation period, it islikely that a row of the array stimulator and an edge of an implantedIPC will approximately align. In this example, within the 30 minutestimulation period this stimulation protocol at least 10 minutes shouldbe well paired with an eTENS system component. Additionally, rather thanusing entire rows during an activation, the array stimulator canactivate the electrode contact elements 1-4 of row 1, elements 5-8 ofrow 4, and elements 9-12 of row 8. Rather than horizontal rows, the gridstimulator can also activate other patterns such as a diagonal row inorder to provide stimulation arrays that are oriented correctly withrespect to the edges of the IPC. Lastly, the grid array can usearbitrary patterns rather than rows and the grid elements do not need tobe square.

The width of non-conductive surface 97 can be set to provide improvedstimulation by an IPC. For example, the data of FIG. 3A to FIG. 8B,support an embodiment of a method having a Step 1 in which an aspectsuch as the width or length of the IPC is adjusted/selected in relationits implanted depth (i.e., distance from a cutaneous stimulator to theIPC). In step 2 a physical characteristic of at least one stimulator(e.g., the distance between the edges of the stimulator and a secondstimulator, or the location of an edge of the stimulator) can then beset according to at least one physical aspect of the IPC (e.g. IPClength) in order to provide for “pairing’ and improved activation of thetarget nerve. In step 3, treatment is provided to the IPC using at leastone suitably paired stimulator.

The modules described for the apparatus 50 are for illustration purposesonly and the device 50 used by the system of the present invention canbe realized with less than or more than the modules and systemcomponents shown in FIG. 18a or 18B and described in this specification,or can be realized in alternative embodiments. For example, rather thanhaving a protocols and parameters module 66, the information related tostimulation protocols and parameters can be simply stored in the memorymodule 60. Similarly, rather than having a stimulation module 54 and awaveform generator module 62, equivalent functionality can be realizedan AD/DA module 64 which contains these modules and all other necessaryhardware, software and/or code required to provide stimulation andsensing. Accordingly, in device 50, disclosed components may be omittedand modules may communicate with, and share, resources of other modules.Any of the modules of the device 50 shown in FIG. 18a , can be realizedpartially or fully in the physician/patient programmer 70, or EXD 72, orneurostimulation system of FIG. 18b . The modules may be within thedevice 50 housing or may exist externally and communicate with wired orwireless manners.

The apparatus 50 may be realized as a portable or desktop instrumentthat controls accessories. The system can be implemented, at least inpart, as customized hardware that plugs into a port of an smart-phone ortablet computer or which communicates with the smartphone or computer sothat some of the modules shown in FIG. 18a are realized by the smartphone or computer. The device 50 should have accessory ports, such asUSB ports, to allow wired communication and connection to other systemcomponents and accessories.

The device 50 can use stimulators incorporated within the housing itselfrather than being connected to the device 50 by wires. In one example ofthis type of embodiment the stimulators can be configured as re-usableelectrode stimulation plates rather than disposable electrodes. Theapparatus 50 may also use percutaneous stimulators including needleelectrodes. The apparatus 50 may be realized using electricalstimulators distributed by companies such as Uroplasty and Electrocoreand Medtronic for providing various types of stimulation includingelectrical and magnetic stimulation. In alternative embodiments of theinvention, the stimulators can be configured to work with IPCs orimplantable active components (IACs) such as those which aremagnetically driven. Stimulators used by the device 50 can be coilswhich induce magnetic fields in and around the implantable componentsand/or in the tissue itself. In general, it is obvious with respect toproviding therapy, that either an IAC, IPC, or conventionalneurostimulation system which uses an implantable pulse generator andstimulator electrode, with at least one contact, can all be usedrelatively interchangeably in order to provide stimulation using theprotocols and nerve targets disclosed herein.

The transcutaneous tissue stimulation system can contain a signalgenerator for generating a stimulation signal. The signal generator canprovide a stimulation signal that is appropriate for at least onemodality of stimulation such as electrical, magnetic, (ultra)sonic,optical, thermal, or other method of stimulating tissue directly, incombination with an IPC, or IAC. At least a first stimulator, coupled tosaid signal generator, is also provided and adapted to be positionedadjacent to a patient to provide a signal to modulate target tissue inthe patient. In an embodiment at least a first IPC is located adjacentto or contiguous with a target tissue for enhancing the modulation ofsaid target tissue by the signal provided by the stimulator. Thestimulator and IPC can be paired so that modulation of tissue isenhanced relative to the modulation that occurs in the absence of theIPC.

In an embodiment where a stimulator provides magnetic or electricalstimulation transcutaneously, the IPC is configured with at least aportion that is electrically conductive. A device that is configured toprovide magnetic stimulation to tissue, having a stimulator that is atleast one stimulation coil, is disclosed in U.S. Pat. No. 8,052,591entitled “Trajectory-based deep-brain stereotactic transcranial magneticstimulation”, and in US2013/0317281 entitled “Transcranial magneticstimulation for improved analgesia”, and in U.S. Pat. No. 6,453,204entitled “Magnetic electrode for delivering energy to the body”, and inU.S. Pat. No. 8,676,324 entitled “Electrical and magnetic stimulatorsused to treat migraine/sinus headache, rhinitis, sinusitis,rhinosinusitis, and comorbid disorders”, in US2014/0247438 entitled“Systems and methods for vagal nerve stimulation”, and in U.S. Pat. No.8,435,166 entitled “Method and Apparatus for magnetic inductiontherapy”, all of which are incorporated herein by reference in theirentirety for all purposes, and may be realized as part of the system ofthe current invention. When a magnetic coil is used to provide amagnetic field, the signal generator 62 may serve as an impulsegenerator capable of powering the magnetic coil stimulator.

In an embodiment where the stimulator provides sonic stimulation, theIPC is configured with at least a portion that is responsive to thesonic stimulation signal. For example, the IPC can be configured with aportion that has physical characteristics (size, density, shape,structure) that allow it to absorb, reflect, or resonate with the soundenergy more than human tissue in order to enhance modulation of activityof adjacent nerve tissue. A device that is configured to provideultrasonic stimulation to tissue is disclosed in US20140194726 entitled“Ultrasound Neuromodulation for Cognitive Enhancement”, in WO2014127091entitled “Transcranial ultrasound systems”, in US20110270138 entitled“Ultrasound macro-pulse and micro-pulse shapes for neuromodulation”, andin US20110190668 entitled “Ultrasound neuromodulation of thesphenopalatine ganglion”, which uses at least one stimulator which is anultrasound transducer coupled to a signal generator 62, all of which areincorporated herein by reference in their entirety for all purposes, andmay be realized as part of the system of the current invention.

In an embodiment where the stimulator provides optical stimulation, theIPC is configured with at least a portion that is responsive to theoptical (e.g., laser) stimulation signal. For example, the IPC can havea portion with characteristics (size, shape, structure, reflectance,absorption) that allow it to absorb or reflect the optical energy morethan human tissue in order allow the IPC to modulate the activity ofadjacent nerve tissue. A device that is configured to provide opticalstimulation to tissue is disclosed in U.S. Pat. No. 8,715,327 entitled“Baroreflex modulation using light-based stimulation”, which usesstimulators which are light sources such as diodes, incorporated hereinby reference in its entirety for all purposes, and may be realized aspart of the system of the current invention.

When the IPC is used in conjunction with electric, magnetic, sonic, orlight based stimulation, it may be realized as a nerve cuff, a solidrod, a hollow rod, a mesh structure, or other structure that allows theIPC to enhance the modality specific energy that is supplied by at leastone transducer that serves as a stimulator of the invention.

The methods and systems for providing enhanced electrical stimulationprovided by one or more IPCs, relative to what occurs without at leastone IPC, is termed “eTENS”. When the stimulator and paired IPC utilizeultrasonic tissue stimulation this is known as termed “eUltrasound”,when the stimulation modality is light it is termed “eLaser”, and whenthe modality is a magnetic field applied to tissue targets, which may ornot also require transmission of the magnetic field through the cranium,it is known as “eTMS”. The use of a passive element to enhance, focus,bias, or otherwise enhance the effect of externally applied stimulationto the modulation of tissue may be extended to other stimulationmodalities as well.

A method of providing transcutaneous nerve tissue stimulation cancomprise operating a signal generator 62 for generating a stimulationsignal and operating at least a first stimulator coupled to saidelectrical generator 62, and positioning the stimulator adjacent to apatient to provide a signal to modulate a tissue target in the patient,and implanting an IPC adjacent to or contiguous with a target tissue forenhancing the modulation of said target tissue by the signal provided bythe stimulator. The stimulation signal provided by an electric,magnetic, optical, or ultrasonic transducer may cause enhancedmodulation of tissue relative to modulation in the absence of the IPC.

FIG. 18b shows a stimulation system configured to provide electricalstimulation to a tissue target, such as tissue near an IPC and may berealized by an implanted device 110 such as an implantableneurostimulator such as that used deep brain stimulation or spinalstimulation. The implanted device 110 has all the electronics typicallyprovided in a modern implantable neurostimulator including components toprovide for control 52, stimulation 54 which may include chargebalancing circuitry to deter problems at the electrode tissue interface,as well as a safety circuitry such as a current limiter, communication68, timing 56, and power supply 74 which may include both a battery andcoil-based and/or antennae-based recharging circuitry for obtainingwireless power. Sensing capacity may also be provided via a sensingmodule 55 which may contain, for example, accelerometers, angle/positionsensors, and which can communicate with sensors disposed on the housingof the device 110. Similar to the stimulation module 54, the sensingmodule 55 may communicate with a conduit 114, connected to the deviceheader port 112, or an accessory port. The other modules shown on thedotted box on the right side of the figure that may serve an implantabledevice were already reviewed in FIG. 18a . The implanted device 110 willhave ports 112 for securely connecting to an electrical conduit 114(which may have an intervening connection member 115 to connect varioustypes of implantable electrode conduits and sensors) and forcommunicating stimulation pulse waveforms along the length of theconduit to at least one stimulator 116 such as stimulation electrodewhich contains at least one contact, but often multiple contacts, toenable bipolar stimulation to occur. In FIG. 18b there are multiplecontacts at the distal tip of the conduit 114. In an embodiment of theinvention where at least one IPC is used with the implanted device 110but is not connected to the device, the IPC would preferably have alength that was set proportionally to the inter-contact distance betweentwo of the contacts of the stimulator 116, and preferentially the IPClength would be the same as the inter-contact distance. Further it wouldbe preferable for the edge of at least one IPC to be aligned with theedge of one of the stimulation contacts. In the case of monopolarstimulation (e.g., tip to can) the electrode contact may be made to belonger than the length of the IPC. In this embodiment, the IPC serves tostimulate a tissue target that is not immediately adjacent to astimulator lead physically connected to the neurostimulator by way of aconduit.

The implanted neurostimulator device 110 may be any approved device onthe market, such as the Restore™ Neurostimulator, which can adjust thestimulation in the treatment of chronic pain based upon factorsincluding a patient's posture (e.g. sitting to lying down, from lyingdown to standing up). The apparatus may be realized by a device such asthe InterStim® System for Sacral Neuromodulation, the Neuropace systemfor providing responsive neurostimulation to the brain in the treatmentof epilepsy, or vagal nerve stimulation systems provided by Cyberonicsfor the treatment of, for example, epilepsy and depression. In anembodiment, rather than being located in, or near, the torso to providespinal stimulation, the neurostimulator is located in a lower limb sitesuch as between the ankle and the knee. A microneurostimulator such asthe BION can also be used.

FIG. 19 shows a schematic of an external electrical nerve stimulator 120which may be used with either cutaneous or percutaneous connections torealize the current invention. For example, the stimulator can providefor percutaneous stimulation to electrodes 122 a, 122 b to stimulate thenerves (e.g., lumbar or sacral) of a patient (such as may occur during atrial stimulation period to assess patient response to stimulation atone or more candidate sites). An external neurostimulator 50 can alsoprovide stimulation conduits 84 that terminate with cutaneous electrodes130 placed superficial to one or more IPCs 131 a, 131 b implanted on ornear spinal nerve roots such as the sacral or lumbar nerves. The IPC maybe placed near the stimulation electrode contacts 130 and may be of aselected shape, orientation, and distance from the stimulationelectrodes, according to the principles and innovative models of thecurrent invention, so that target nerves may be selectively stimulatedwhile minimizing or preventing the activation of nearby nerves which arenot targets of the stimulation. Some leads and methods of implantingleads for stimulating targets such as spinal root targets have beendisclosed in US APP Nos. 20140343656 (to Wechter), 20140324144 (to Ye),20140324133 (to Deisseroth), and 20120203308 (to Gerber),PCT/US2014/029683, (to Perryman), and 20140081363 (to Clark), which maybe used by the current invention and are all incorporated by referenceherein. For example, the type of stimulator, applicator, and supportingstructure disclosed in US 20010025192, entitled “Single and multi-polarimplantable lead for sacral nerve electrical stimulation” can be usedfor stimulation of various spinal roots disclosed herein, and isincorporated by reference. It is understood that any embodiment using anerve cuff that uses an implantable neurostimulator may use aconventional lead rather than a nerve cuff without departing from theinvention.

In an embodiment, percutaneous stimulation electrodes 122 a, 122 bstimulate nerve cuff IPCs 10, 131 b located at lumbar and sacral nervetargets, respectively. If either or both sites are found to be usefulthen a neurostimulator can be implanted and attached to the nerve cuffsto continue therapy. Alternatively, the IPCs may be operated as an eTENSsystem in conjunction with an external cutaneous stimulator (similar to130 but not shown to avoid cluttering of the figure) which receivesstimulation signals from an external device 50.

Differentially activating one or more subsets of neural pathways withIPC technology can provide the advantages of (1) improving modulation ofa selected therapeutic outcome, (2) decreasing at least onestimulation-evoked side effect, (3) providing concomitant, but unique,stimulation related to each of a plurality of IPCs in order to providefor selective modulation of physiological responses associated withspecific somatic or autonomic nerves, such as areas along these nerves(4) providing concomitant, but unique, stimulation to inhibit one ormore physiological responses associated with somatic or autonomic nerveswhere IPCs have been implanted, (5) providing a mixture of stimulationwhich serves to both activate and inhibit different physiologicalresponses (direct or reflexive) associated with either somatic orautonomic nerves or both, and (6) provide for improved selectivemodulation of specific motor responses and response pathways. In oneembodiment, selective nerve activation is achieved by managing therelationship between the physical dimensions (e.g., length) of one ormore IPCs to approximate dimensions of one or more correspondingstimulators. This relationship can follow principles derived using, forexample, the results of FIG. 4 to FIG. 8.

FIG. 20A shows embodiments of a system configured for selectiveactivation of multiple neural targets (labeled Nerve 1 and Nerve 2). Thesystem (or a model simulating the system) can be comprised of two ormore IPCs placed in close proximity to, or around, nervous tissuetargets to assist in providing selective activation of a single orplurality of nerves or tissue located within the body (e.g., muscle,connective, and fat tissue). In an embodiment this strategy can beimplemented using bipolar electrodes, where the IPC lengths (L1b, L2b)are approximated by the distance between the surface stimulatingelectrodes (D1a, D2a). All electrodes, and IPCs that run along thelength of the nerve, may be positioned in relation to proximal end (Pe)and distal end (De) of each system component. The depths of the IPCsfrom the skin surface (D2a, D2b) may be varied. At least one of thelength, thickness, shape, conductivity, and edge position of an IPC canbe set (“paired”) according to other system characteristics, forexample, the distance from the surface, position of stimulator edges,distance between the surface stimulators, or other dimensions of one ormore surface stimulators according to the findings of the currentinvention related to enhancing nerve modulation. The surface stimulatorscan be connected to sources of energy such as stimulus generators, andmay be configured to reside on a single non-conductive support backingstructure in order to maintain appropriate inter-stimulator spacing andorientation (e.g. D1a). Although the orientations of the stimulators areshown as all the same and are aligned with the edges of the IPCs, it maybe that angling one or more stimulators by an amount, for example+/−30%, may increase the probability that a portion of an edge of asurface stimulator will intersect an edge of an IPC, and this may befound to be a preferred embodiment because it facilitates setting up thesystem with less accuracy needed with respect to edge position. Thesystem can enable the activation of a single nerve bundle using a givenset of stimulation parameters (e.g. particular amplitude, frequency,pulse width, bursting pattern, duration, waveform, and duty cycle), ormodulate two or more different neural pathways with the same ordifferent sets of stimulation parameters. Surface stimulators 1, 2 and 3can be independently operated, or stimulator 2 can be a common returnfor stimulator 1 and 3. When used to stimulate nerves such as thosebelow the knee, the system configuration can be realized for both legsof a patient to provide bilateral stimulation.

FIG. 20B shows another embodiment of selective nerve activation byenhanced transcutaneous nerve stimulation (eTNS) through the use ofmonopolar stimulating surface electrodes 138 a 138 b. The physicaldimensions of each IPC 134,136 and the corresponding “paired” electrode(138 a and 138 b, respectively) are selected to match in order toprovide selective eTNS (i.e., improved neural excitability of selectedneural targets). In this case, the lengths of the two passive IPCs 134,136 (realized as nerve cuff form factor placed around nerves 1 and 2)are L1b and L2b, respectively. Selective activation of each individualnerve is achieved by applying electrical pulses (transcutaneously)through surface electrodes 1 and 2, where selective enhancement can beimproved by matching the edges of the IPC+stimulator pair. Thestimulation delivered through each surface electrode will, in turn,primarily result in the corresponding generation of action potentials ineach respective nerve. In an example monopolar embodiment, at least theproximal edge (“Pe”) or distal edge (“De”) of the IPCs is preferablyaligned with an edge of a corresponding surface electrode.Correspondence, in the lengths of the stimulator and IPC “pair” a wellas the alignment of the edges of the IPC and surface electrode, can bean important factor for improving selective activation of individualnerves in some monopolar and bipolar embodiments. Although in the figureL4a and L1b appear about the same length, L4a may be larger or smallerthan L1b (i.e., stimulator length may be >, =, or < compared to IPClength). A stimulator-IPC pair can be matched to provide enhancedstimulation according to the principles of the current invention. Allthe physical parameters of the stimulation system can be simulated usingthe models disclosed in this invention in order to determine improvedimplementations within individual patients.

FIG. 21 shows a schematic of system embodiments for activating nerves ofthe head, neck and upper chest, such as those of the autonomic nervoussystem. The system may be implemented for stimulating the vagus nerve140 for treating epilepsy, migraine, blood pressure, depression, orrespiratory disorders using IPC #1 142 a. A second IPC 142 b is shownimplanted to activate sympathetic nerves within brown adipose tissue or“BAT” 148 (e.g., at a supraclavicular location) to treat obesity.Surface electrodes 1 150 a and 2 150 b are illustrated contralateral tothe corresponding implanted IPCs in order to avoid cluttering of thefigure, but would typically be located ipsilateral and appropriatelyaligned with the IPCs according to the inventive principles.

Selective activation of either the vagus nerve 140 (or selected fibers)or nervous tissue within the BAT 148 can be achieved by stimulatorelectrode 1 150 a or electrode 2 150 b, respectively, either of whichmay serve as anode or cathode. In a monopolar configuration the returnsurface electrode for either electrode 1 or electrode 2 can be placed onan anatomically appropriate location selected to cause minimal unwantedphysiological or sensory activity at the return electrode site (e.g.,tingling). The return electrode may be placed on the upper shoulder orhip. Electrical stimulation can also occur in a bipolar fashion, whereeach surface electrode is bipolar (with 2 contacts of opposite polarity)and is preferably placed such that at least one edge of a contact isaligned with one of the two edges of an IPC (see alignment of IPC #2with stimulator #2 in FIG. 20A).

BAT stimulation may comprise placing a pair of surface electrodeslaterally, relative to the IPC, whereas vagus nerve stimulation couldcomprise the placement of a pair of surface electrodes both rostral andcaudal to the IPC. In another embodiment, two IPCs can be surgicallypositioned bilaterally (e.g., to stimulate left and right cervical vagusnerves). Activation of vagus nerve, or the autonomic nerves locatedwithin the BAT, can be achieved in a monopolar fashion where a firstsurface electrode is placed over the left IPC and a second electrode(i.e., return) is placed over a contralateral IPC. Each surfaceelectrode can serve as an anode or cathode. To assist with spacing, twoor more electrodes can be positioned on a non-conductive support backingstructure such as a foam pad, and each contact can be connected to anelectrical source of the respective polarity.

In an embodiment, the IPC #3 142 c may be placed in the upper throat orlocations in the head, face, or ears to treat disorder such asobstructive sleep apnea and headache as will be disclosed. In anembodiment, a magnetic stimulator 152 may induce a field in tissue nearthe IPC which causes an electrical field in the tissue and allows forselective activation of a tissue target.

Active and Distributed Embodiments

Although the systems and methods shown here do not have a pick-upelectrode that is routed to a stimulation electrode, the findingsreported here may have implications for such as system. In an embodimentthe principles of the current invention, can be used to configure andimprove a stimulation router system (SRS), such as that described inU.S. Pat. No. 8,332,029 entitled “Implant system and method usingimplanted passive conductors for routing electrical current” toGlukhovsky, which is assigned to Bioness Inc. For example, the “pick-upelectrode” of the SRS may be configured for receiving a field providedby at least one selected stimulator in a manner according to the currentinvention. For example, the SRS may include a component that hasphysical dimensions and alignment with at least one external stimulatoraccording to the principles of the current invention.

In an embodiment, an IAC can be realized as an implanted neurostimulatorthat obtains its power from an external magnetic stimulator and isprovided with circuitry to convert the magnetic to electrical energy.Although the magnetic stimulator 152 and IPC #3 142 c of FIG. 21 uses apassive IPC, an alternative embodiment may use a stimulator 152′ that isconfigured to work with an IAC having active components 142 c′ such as awireless power receiver 544 and related circuitry for controllingharvesting of magnetic fields to produce electrical stimulation signals.Either system may be operated using methods such as that shown in FIG.22b which, in an embodiment, provides stimulation with an IPC for aselected duration in order to determine if a (typically larger) deviceshould subsequently be chronically implanted in the patient, such as animplantable chronic vagal nerve stimulator. Embodiments of the currentinvention that are related to screening can be realized using a systemakin to the magnetically powered neurostimulator disclosed in US App.20130310895 entitled “Neurostimulator system apparatus and method” orthe magnetically powered neurostimulator disclosed in US App.20120101326 to Simon et al, entitled “Non-invasive electrical andmagnetic nerve stimulators used to treat overactive bladder and urinaryincontinence”, incorporated herein by reference in their entirety forall purposes.

The generation of electric fields designed to penetrate interveningtissue may be provided by surface stimulators configured to generate anelectric field with field lines extending generally in the longitudinaldirection of one or more nerves to be modulated. In embodiments,stimulators may be separated along the longitudinal axis of a tissuetarget such as a nerve to facilitate generation of such an electricfield. The electric field may also be configured to extend in adirection substantially parallel to a longitudinal direction of at leastsome portion of the tissue or nerve to be modulated. For example, asubstantially parallel field may include field lines that extend more ina longitudinal direction than a transverse direction compared to anerve. Orienting the electric field in this way may facilitateelectrical current flow through a nerve or tissue, thereby increasingthe likelihood of eliciting an action potential to induce modulation.Accordingly, in an embodiment, the orientation of at least one IPC isoriented along the length of a nerve in order to remain effectivelypaired with at least one stimulator, that is similarly oriented, inorder to provide for enhanced stimulation of the nerve.

Tissue Modulation for Screening and Treatment.

In an embodiment an IPC 10 may be configured for implantation in asubject in a location that permits the modulation of target tissue whichis a nerve 12 situated such that intervening tissue exists between theIPC 10 and the nerve 12. Intervening tissue may include muscle tissue,connective tissue, organ tissue, or any other type of biological tissue.The location of IPC 10 does not require contact with nerve 12 forachieving effective neuromodulation. However, placement of the IPC 10located directly adjacent to nerve 12 is preferred for effectiveneuromodulation, such that little intervening tissue exists. During animplantation procedure locations and amounts of stimulation can betested for the IPC 10, in order to assess suitability of variousstimulation protocols, implant sites, response to stimulation, oreffectiveness of therapy. Candidate locations for the stimulator mayalso be assessed. The IPC and stimulator “pair” can be sequentiallytested and adjusted until a set-up is found that provides sufficientstimulation of a tissue target to meet a selected or therapeuticcriterion. Additionally different sizes, shapes, and numbers of IPCs andstimulators may be assessed during the implantation procedure.

A stimulator 14 can be configured for use at a location external to apatient 8, either directly contacting, or close to the skin 20 of thepatient. A stimulator providing a magnetic field to tissue near an IPC,or to the IPC itself, does not need to reside directly upon the skin.Alternatively, the stimulator 14 may be configured to be affixed to theskin 20 of the patient via adhesive, or an elastic band, sock or othersecuring mechanism that serves to hold stimulator 14 in place. Thestimulator 14 should be placed so that it is paired with the IPC bybeing suitably positioned, oriented, angled, and/or configured withphysical dimensions so that the IPC effectively provides enhancedmodulation. The dimensions of at least one IPC and at least onestimulator may be adjusted or selected according to the distance thatwill exist between these two system components during stimulation of apatient.

Screening.

As a screening method eTNS has advantages over using percutaneousstimulation (PNS). Once the IPC is implanted, its effect can remain veryconstant with respect to increasing the activating function of aparticular portion of nerve proximate to the IPC. In the case of PNS,the needle must be inserted and correctly positioned within thesubcutaneous space at the beginning of each stimulation session.Additionally, eTNS can allow a screening period to occur at home becausethe patient is not required to undergo repeated piercing of the skin.Accordingly, the eTNS allows screening/treatment procedures which mayinvolve more frequent nerve stimulation. Treatment may occur multipletimes during the day or daily over several months. This is difficultwhen clinical visits are needed. Further, if a stimulator is affixed toa person's skin in order to stimulate during normal daily-lifeactivities (perhaps for several hours each day) then eTNS providessignificant advantage over PNS since it can occur for long periods oftime without inconveniencing the patient. Since implantation of anexpensive, chronically implanted neurostimulator is more invasive, thequick and easy implantation of an IPC may be desirable by patients anddoctors as a first step in determining a proper therapy course. Evenmore so when the IPC is embodied as a simple, inexpensive, conductivecuff eTNS also offers advantage over approaches that require a temporarypercutaneous leadwire since the IPC approach has less risk forinfection. The IPC used during screening can be configured as a nervestimulator electrode having a connector (e.g. IS-1 adaptor) that can beconnected to an implanted device if the screening results determine thata fully implantable, chronic stimulator is warranted.

In an embodiment, at least two different IPCs can be used for screeningor treatment therapy. FIG. 22A illustrates a method of implanting afirst 200 and a second 202 IPC of lengths L1 and L2, and then situatingat least a first and second stimulator 204 so that it is possible tostimulate a first IPC and second IPC, respectively. After the componentsare paired, treatment can be provided by at least one of the two pairedstimulator-IPC pairs 206,208.

FIG. 22b illustrates a method of using eTNS as a method of screeningtreatment candidate patients who might benefit from various types andmodes of neuromodulation therapy (e.g., fully implanted systems). In anembodiment, a method comprises the step of implanting, within thepatient, at least one conductive implant proximal to an anatomicaltarget of the patient 210. The target is selected as a candidate therapytarget which will be assessed during the steps of the method. The nextstep 212 is to provide at least one stimulation signal to the patientfrom a stimulator located outside of the patient according to ascreening protocol. There is also step of assessing the patient responseto the provision of the stimulation signal provided in accordance withthe screening protocol to produce a screening result 214. The screeningresult can be calculated from a comparison of data before and afterstimulation, or may include an assessment of data from before, during,and/or after the stimulation takes place. The screening result can becalculated on data from a single stimulation session or from multiplestimulation sessions, across weeks or months, during which either thesame or different stimulation parameters were used. In the screeningmethod, if the screening result is positive then at least one positivescreening outcome activity is performed 216. Alternatively, if thescreening result is negative then performing at least one negativescreening outcome activity 218 is performed. Positive results may beobtained when screening results are compared to at least one screeningcriterion and the data successfully pass the at least one screeningcriterion. Negative results may be obtained when screening results failat least one screening criterion. A screening criterion may be forexample, the reduction or increase of a selected type of activity orcondition, such as a specified reduction in the number or severity ofbladder leaks, episodes of urinary urgency, or headaches are experiencedby a patient over a given time period. Examples of positive and negativescreening outcomes are now provided.

The method may include, for example, a positive screening outcomeactivity 216 which includes implanting a fully implantable stimulationsystem in the case where the patient met at least one screeningcriterion. The positive screening outcome indicates that a fullyimplantable system is indicated. Since the patient positively respondingto eTNS is interpreted to support that the patient is a good candidatefor a more invasive stimulation system.

An alternative positive screening outcome activity 216 is to not implanta more invasive stimulation system. Since a patient met at least onescreening criterion the patient any not require a fully implantable, ormore invasive, stimulation system. Accordingly, depending upon the aimof the screening test, a positive result may indicate either that afully implantable system is warranted or that a transcutaneous or eTNSsystem is sufficient.

In an embodiment, the determination of a clinically appropriateintervention may include a series of screening tests. Initially, astandard type of nerve stimulation is used and based upon the results ofthat first testing, an eTNS may then be assessed. Based upon the eTNStesting, either the standard, eTNS, or fully implanted system may beselected. If a patient does not respond to either TNS or eTNS, then nosystem may be implanted. Further, if both conventional and eTNSstimulation fails to meet at least one screening criterion then adifferent mode of therapy may be warranted—such as implanting a brainstimulation system if eTNS vagal stimulation did work. This can benefita patient since they skip being let down by being refractory to animplanted vagal stimulation system.

A method may include, for example, a negative screening outcome activity218 of implanting a fully implantable stimulation system if a patientfailed a screening protocol. In this case, screening is negative becausethe patient failed to meet at least one screening criterion. Thisoutcome may result in providing the patient with a different therapy,may indicate drug therapy should be simultaneously provided, mayindicate an IPC location should be changed and the screening protocolredone, may indicate the stimulation protocol parameters should beadjusted a second screening test is done, or may indicate otheralternative treatment paths are merited.

In an embodiment, a negative screening outcome activity 218 includesclassifying the patient as a non-responder and seeking another type oftreatment. Alternatively, a negative screening outcome activity includeschanging the stimulation protocol and providing a second screeningregimen. The change in the stimulation protocol 220 may include a changein stimulation site where the implant is located. If more than one IPCwas implanted changing the stimulation protocol may simply includechanging the location of the external stimulator in order to stimulate adifferent IPC. The change in the stimulation protocol may include achange in stimulation signal including for example, at least onestimulation parameter such as stimulation amplitude, frequency,inter-stimulus interval, duration, and number of treatment stimulationsprovided within a day, week, or monthly period.

Screening test results may be interpreted in the larger clinical contextof a patient. Information such as history of response topharmaceuticals, the patient's age, symptoms, preferences, and issuesrelated to comfort may all play a role in determining how the results ofthe screening test are used to adjust subsequent treatment. If severalscreening criteria are used in a screening test then these may beevaluated together. For example, a first screening criterion may be usea smaller threshold than a second screening criterion. A patient maypass a first screening criterion, indicating that the patient isresponsive to, for example, vagal nerve stimulation with an IPC, but mayfail to pass a second screening criterion suggesting that an implantedsystem rather than an eTNS system is merited, or that an eTNS ratherthan TNS system is required. The external stimulator used in thescreening may be an electric, magnetic, sonic, or other stimulatorexternal to the patient.

A screening test may be useful as a measure which serves as an inclusioncriterion in a clinical trial. For example, only patients who respond toeTNS therapy may be considered candidates for a permanently, and fullyimplanted nerve stimulator. In this manner, a clinical study for apermanent nerve stimulator will not include patients failing to respondto eTNS and thereby the trial may be able to show a larger treatmenteffect.

In one embodiment, a method of screening patient for eTNS, can comprisethe steps of providing at least one stimulation signal 212 to thepatient from a stimulator located outside of the patient according to ascreening regimen, assessing the patient response 214 to the provisionof the stimulation signal provided in accordance with the screeningregimen to produce a screening result; and assessing the screeningresult 214 as positive or negative. In the case where the screeningresult is positive 216 then the method includes performing at least onepositive screening outcome activity, while if the screening result isnegative then the method includes performing at least one negativescreening outcome activity 218. In the case of a at least one of apositive or negative outcome activity, the method includes implanting,within the patient, at least one IPC proximal to an anatomical target ofthe patient, the target being selected as a candidate therapy target andconfiguring the stimulator to provide stimulation to the implant. In anembodiment a patent has a brain disorder and the stimulator can be atranscranial magnetic stimulator. The IPC can be implanted within tissuethat is at most 2 inches from the surface of the cortex (or 2 inchesfrom the scalp). An IPC can also be implanted on, or within, a corticaltarget in order to enhance either TENS (e.g., tDCS or tACS) orelectrical convulsive therapy (ECT) in the treatment of disorders suchas depression.

Regardless of the screening test, test results can be computed upon apatient's subjective assessment of symptoms or upon evaluation ofmeasured data such as sensed physiological data including electricalbrain activity, cardiac activity, blood pressure, a measure of the eyesuch as pupil dilation, heart rate, or other features which may be usedto assess the patient. When the test results are computed upon measureddata, sensing 55 and processing 58 modules of a device 50 may providefor the data collection and assessment.

Implantable Component Designs.

A number of illustrative IPC designs are shown in FIG. 28 to FIG. 31 ofthis application. The IPC may be constructed in alternative shape andstructures in different orientations than those shown here forillustration. Some IAC designs, such as that seen in FIG. 33 can bepowered by a device that uses magnetic or RF means to power the IAC ofthe stimulation system, as is disclosed in US 20130085545, entitled“Electrode Configuration for Implantable Modulator” and US 20130079843entitled ‘Apparatus and methods for feedback-based nerve modulation”,both to Mashiach, incorporated herein by reference in their entirety forall purposes.

Although, unlike various embodiments of the IPC of the currentinvention, the Mashiach technology relies upon conversion ofelectromagnetic signals for all of the embodiments of his invention,some of the principles for the electrode design disclosed by Mashiachare relevant to embodiments of the systems and methods of the currentinvention both for implementations that use electromagnetic signals andfor those that simply use electrical signals provided from an externalstimulator in the eTENS embodiments.

As shown in FIGS. 28a-e , The IPC 10 may include one or more structuralelements to facilitate implantation, orientation, and securing of theIPC 10 into the tissue of a patient 8. The securing element(s) 517 mayinclude, for example, suture holes, elongated anus, flaps, surgicalmesh, biological glue, hooks or spikes of flexible carrier which serveto anchor the IPC to tissue. The anchor elements can facilitatealignment of the IPC 10 in a desired orientation within the patient. Inan embodiment, IPC 506 may include a deformable elongated arm 530 havinga two wing anchor such as a first extension 532 a and a second extension532 b for increased stability. The anchor elements 532 a and 532 b aidin securing and orienting IPC 506 with respect to a target andstimulator. The elongated arm 530 enables the IPC to be secured slightlydistally to soft or hard tissue targets (e.g., nerve, bone, or muscle,etc.) beneath a patient's skin. The IPC 10 may be formed as, or may beadjusted prior to surgery to assume, various shapes such asapproximately an elliptical, circular, annular, cylindrical, orrectangular shape, or a shape that is determined based upon a particulartarget in patient. In embodiments, the shape, size, orientation,rigidity and other characteristics of the IPC can be selected oradjusted to facilitate orientation of the IPC with respect to aparticular tissue target to be modulated, the shape of a stimulator,alignment of a stimulator, imaging data or measurements of a patient, orthe distance between a stimulator and IPC. When embodied as a fully orpartially cylindrical nerve cuff, the two opposing edges of the cylindermay be perpendicular to the IPC length, or at least one may be angled.Further, a beveled, pointed, or rounded, rather than flat, edge may berealized.

FIG. 33 shows an implantable active component (IAC). An IAC may berealized as a microneurostimulator embodied as a small rod form factorthat can be implanted in a patient, but in a simple embodiment may be anIPC having at least one active component such as RFID circuitry, ratherthan being a completely passive IPC. In a more comprehensive embodiment,an IAC has components such as a wireless power receiver module which maycontain an antenna, rectenna and/or coil 544 disposed along or outsideof the housing of the IAC, electrode contacts 546 a,546 b that may berealized on the IAC housing or at the distal end of a lead, and moduleshaving circuitry related to providing wireless power harvesting andconversion (wireless power module 548), communication 550, safety andpower regulation 552, an identification information module 554 includingan RFID chip, memory 556 for storing protocols and information, andcontrol 558. The module circuitry may be mounted on, attached to, orintegrated into the IAC, and/or conduits that communicate to the housingsuch as multi-contact electrode leads, and/or contained within the IAChousing 560, when housing is provided. The modules may be configured foroperation and data/power communication in collaboration with an externalneurostimulator device 50 in order to realize a treatment protocol andto be controlled by the external device. Sensing modules may also beincluded in order to provide sensing of sensed signals from a patient 6.Various circuitry and connectors may be used to connect circuitry to theIAC electrode contacts 546. To protect various IAC components from theenvironment within a patient's body, at least a portion of the IAC andor some of its components may include a rigid or non-rigid housing, aprotective coating, and/or a non-conductive support member. In someembodiments, the protective coating/outer layer may be made from aflexible material to enable bending of components such as the electrodeleads. In embodiments, the protective coating and/or housing may includefor example, an alloy, silicone, silicone rubber, and silicone withpolytetrafluoroethylene polyimides, phenyltrimethoxysilane (PTMS),polymethyl methacrylate (PMMA), Parylene C, liquid polyimide,polyurethane, laminated polyimide, polyimide, Kapton, black epoxy,polyether ketone (PEEK), Liquid Crystal Polymer (LCP), or any othersuitable biocompatible coating such as selected from the groupconsisting of lubricious PVP, antimicrobial and anti-inflammatorycoatings. In embodiments, the protective coating may include a pluralityof layers, including different materials or combinations of materials indifferent layers.

The IACs and IPCs may have circuitry and include electrodes made ofconductive materials, such as gold, platinum, titanium,platinum-iridium, galliumnitride, titanium-nitride, iridium-oxide, orany other biocompatible conductive material or combination of materialssuch as hydrogel. The IAC/IPC, including its housing, may be fabricatedwith a thickness and flexibility suitable for implantation under apatient's skin without a large risk of skin erosion. In an embodiment,the IAC/IPC 10 may have a maximum thickness of less than about 4 mm orless than about 2 mm, and the conductive components of the IPC may havea thickness of only 0.02 mm, as supported by the data of FIG. 7.Although the IAC of FIG. 33 is realized as a cylindrical form, which mayapproximate the cylindrical shape, size, and design of a BION or berealized as a neurostimulator such as those disclosed by StimwaveTechnologies SCS neurostimulator (e.g., US Patent App #20140031837,“Implantable Lead”), or Micron Devices neurostimulator (e.g.,PCT/US2014/029683 entitled Devices and methods for treating urologicaldisorders), the IAC components can be formed into a nerve cuff thatwraps partially or fully around a target nerve, or which is designed tocooperate with a nerve cuff or electrode lead to provide electricalstimulation to at least one electrode contact. Percutaneous injection ofan IAC or IPC, in very close proximity to a target nerve is possible,but may be prone to potential migration issues over time. However, insome uses, such as stimulation that will be provided only for days orweeks, migration may not be a large concern. An IPC which is simplyinjected, or has a connection through skin, could be used as a temporarystimulator during initial screening of patients, similar to that usedfor the Interstim System at the level of the spine (and included in step210).

Alignment Strategies.

Some advantages of the current invention rely on an IPC being correctlyaligned with at least 1 external stimulator. FIG. 24a shows a controllerdevice embodied as a smartphone 420 for controlling a stimulator device400 shown in FIG. 24b that may be used by the current invention andwhich is approximated by the GammaCore tissue stimulator. The device 400can have all the components disclosed in, for example, US App20130066392 entitled “Non-invasive magnetic or electrical nervestimulation to treat or prevent dementia”, incorporated herein byreference in its entirety. Alternatively, the stimulator device can beimplemented in a more distributed configuration and incorporate modulesof the device 50 shown in FIG. 18. In an embodiment, two stimulators402, 404 are provided on the stimulator device 400 which can each becomprised of conductive plates and serve as anode or cathode which maybe dynamically assigned using control circuitry of the device 400.Additionally, either stimulator 402,404, may be realized as an electrodegrid array 100. In alternative embodiments, the surface of the platestimulators 402, 404 may be divided into separate regions which may beelectrically active or inactive (e.g. insulated, or floating). Forexample, stimulator plate 404 is shown as comprising a number ofhorizontal contact surfaces 412 each row of which may be individuallyactivated and which may be separated by non-conductive surfaces such asridges. Only a portion of the horizontal contacts 412 may be activatedto determine the functional shape of the stimulator. Further, thehorizontal surfaces 412 can be adjustably activated (by the patient, bythe stimulation protocol, by the controller device 420 or otherwise) sothat these line up well with at least one implanted IPC 10.Additionally, the horizontal surfaces 412 can serve as at least onebipolar electrode having an adjustable inter-stimulator distance. Thestimulator 404 may be rotated (under manual or motor control, whenmotorized adjustment means is provided within the housing of the device400) for example, to align the stimulator contacts 412 and the edge ofat least 1 IPC. Stimulation protocol parameters (provided by the controldevice 420 or device 400, of a stimulation program may directstimulation signals to different contacts 412 at different times duringtherapy delivery in order to increase the likelihood that during aninterval of stimulation the contacts 412 are well aligned with an edgeof an implanted IPC.

The controller device 420 can allow a user to control the stimulationand to align a stimulator and IPC. In an embodiment, a digital camera406 is provided which can capture still frame and video data and thedigital data can then be displayed to a user assist in positioning thedevice 400 correctly. For example, the device 400 can use itscommunication module 68 to communicate with a tablet, smartphonecontroller device 420 configured to operate software related topositioning the device 400 during the provision of therapy.Communication can be wireless using a protocol such as Bluetooth orWi-Fi. Alternatively, communication signals can be sent and receivedusing a physical cable 422 that connects the smartphone controller 420to the device 400, using at least one accessory port 416 on the device400 and communicates, for example, using a USB communication protocol.During operation, the device 400 sends the video data to the smartphonewhich displays images so that the user can see and adjust what area ofskin is being stimulated.

In an embodiment a surgical scar or a permanent or temporary tattooedsymbol such as the “+” symbol may serve as a location marker 424 for anIPC. In FIG. 24a the “+” symbol displayed by the screen of thesmartphone, although the stimulator is not shown being pointed at apatient to avoid cluttering of the figure. There may be 2 markers suchas tattoos in order to more accurately align not only the edge, but theaxis of the IPC with a stimulator of the device 400. In an embodimentthe location marker 424 is electroconductive tattoos and allows for atleast one sensor on the device 400 to issue a signal when a stimulatoror sensor of the device 400 is in contact with the tattoo. In thisembodiment the device 400 is designed to establish a closed electricalcircuit wen correctly aligned with the tattoo that is detected by thedevice 400. For example, an impedance circuit could detect the impedancebetween the two stimulators, which would be significantly lower whenthese each are in contact with an electrically conductive tattoo.Alternatively, the tattoo itself could be designed to work with one ormore stimulators and can serve as an extension of the stimulator that isaligned with an edge of an IPC. In embodiment, the neurostimulatordevice 400 projects on the patients skin a box that serves as a visualalignment signal 426. The signal may indicate, for example, where thestimulation field would be located relative to the target “+”. Visualgraphic signals can be superimposed onto the screen of the smartphone420 such as navigation arrows 428 a and 428 b which can indicate to auser how to position the device 400 so as to achieve correct alignmentbefore delivering stimulation. In other words, the users would attemptto make sure the +symbol location marker 424 resides within the box 426before, and during, stimulation. Further, rather than having a “+”symbol, the device 400 can also provide a location guidance module 408which may comprise circuitry and routines for assisting in aligning thesystem components and may also contain an NIRS sensor and/or laser toassist with alignment (e.g., by detecting the proximity of an artery tothe stimulator). In an embodiment the “+” location marker 424 may begenerated by the controller 420 or device 400 which can optically, orotherwise, detect the position and/or orientation of the IPC 10 and thismay be used to guide alignment. A speaker 430 on the controller device420 may provide auditory guidance cues such as “Please move thestimulator slightly up” or a series of beeps that change in frequency asthe edges of the both a stimulator and IPC become well aligned.

In an embodiment, a processor of the stimulator 400 can analyze thevisual image data collected by digital camera 406 in order select andactivate certain regions of the stimulator plates 402, 404 due toresults of calculating upon the data. The regions activated on thestimulators are thereby adjusted to improve alignment of stimulator andIPC components related to the stimulation of a target tissue. In anembodiment, the device 400 communicate with a tablet or smartphonecontroller device 420 configured to operate to allow a user to modifythe stimulation parameters or protocols. Although the device 400 may beprovided with controls situated on its housing in to adjust thestimulation, elderly or handicapped patients may not easily accomplishaccurate manual control of the stimulation. Using a smartphone or othertype of controller 420 disposed external to the housing of the device400, and connected in a wired (via accessory port 416) or wirelessmanner may provide greater control and a more user friendly experiencethat may increase patient compliance.

In an embodiment, a device similar to the GammaCore can have anaccessory port 416 that is multifunctional. The at least one accessoryport can permit connection to at least one additional system componentsuch as an electrode or other system components or external devices. Astimulator or sensor, such as a disposable electrode, can be attached toa conduit that plugs into the accessory port 416. The device 400, canthen stimulate from at least one stimulator 402, 404 in combination witha third electrode located more distally. This may be useful, forexample, if the device 400 is configured for both stimulation andsensing which occurs before, during, or after the stimulation. The thirdelectrode allows measurement of dipole (of the third electrodereferenced to either 402 or 404) which is larger than that possibleusing 402 referenced to 404, since these may be on the same side of thedipole. In the recording of cardiac or EEG data, this additionalelectrode can provide for improved measurement and functionality. Thismay allow the device 400 to stimulate the vagus nerve and also recordcardiac activity using two or more electrodes which connected to theaccessory port 416 and placed on the subject to robustly measure ECGactivity. The third electrode advantage can be useful for stimulation aswell in the case where 2 fixed stimulators are not preferable. Anotherbenefit is that at least one of the two rigid stimulators 402,404 can beused to stimulate the temple of a subject, while the third electrode maybe situated at the back of the head in order to cause the stimulationsignal to travel from the fixed stimulators to the electrode (i.e. fromthe front to the back of the head or vice versa). This may ensure agreater transmission of the signal into the patient's brain or cranialnerves than may occur using the two fixed stimulators located proximalto each other. At least one distally located electrode may also be usedto provide stimulation to the contralateral vagus nerve, or to provideneurostimulation such as tDCS, either alone or in combination with vagalnerve stimulation.

In an embodiment, the port 416 could be used to record signals from asurface electrode, which could provide a feedback signal (e.g., ameasure such as foot EMG) which can be used for assessing a therapyresponse or aligning the stimulator with the IPC implanted near the PTN.In another embodiment, the EMG electrode can be placed over the larynxto measure vagus nerve activation during eTNS. In an embodiment thedevice 400 is configured with least one fixed stimulator 402, 404, andat least a port communicating via conduit with a least one electrodelocated at least three inches away from the fixed stimulator 402, 404.

FIG. 24c shows an alternative embodiment in which a portable device 400′has been configured with a stimulator 402′ to provide at least one oflaser-, ultrasonic-, electric- or magnetic-based stimulation. Althoughthe stimulator is shown as fixed plate in the figure, the stimulator maybe adjustable with respect to the device 400′ housing. For example,within the housing there may exist movable magnetic coils which may beangled. The coils may be replaceable and adjustable (e.g., a hemholtzcoil may be replaced with a figure eight coil). The accessory port 410is multifunction and may allow for connection and communication to othersystem components that may provide for various stimulators to becontrolled by the device 400′. Although shown as a portable embodiment,the device 400′ may be realized as an office based instrument such asdevice 50. For example, an ultrasound or magnetic stimulator may be muchlarger than the embodiment shown.

FIG. 24d shows an alternative embodiment in which a portable device 400″has been configured to provide stimulation with a modality specific(e.g., light, ultrasonic, electric or magnetic) stimulator 402″. Thedevice 400″ may be configured with at least one adjustable stimulator,such that the angel, active elements, or other characteristics of astimulator may be adjusted in relation to a particular target+IPCcombination so that they are well paired. A method for providingtransdermal stimulation therapy to a subject comprises positioning adevice 400″ with stimulator 402″ over at least one of the top or bottomsurface of a patient's foot or area near the medial malleolus and nearan IPC located near a tissue target, and providing a stimulation signalthrough skin to stimulate the target nerve. In embodiments of themethod, the device is placed on the patient's skin to stimulate one of:an IPC located near the big toe of a subject and the tissue target isthe MPN; an IPC located near the three smallest toes of a subject andthe tissue target is the LPN; at least one IPC located below the medialmalleolus and the target is the MPN and/or LPN; an IPC located cephaladand anterior to the medial malleolus and the target is the SAFN; an IPClocated posterior to the medial malleolus and the target is the PTN. TheIPCs can be implanted in one or both lower limbs of a patient.

FIG. 25 shows an embodiment having a cutaneous, multi-contact arraystimulator 440 that may be used, with the device 400 shown in FIG. 24b ,for example, during vagal or tibial nerve stimulation. The arraystimulator 440 has a series of electrode contacts 442 a-e, all of whichmay be independently activated. If only contacts 442 a and 442 b areused to provide a stimulation signal then this would produce a smallerfunctional stimulation terminal than if 442 a-e were used. Subsets ofcontacts 442 a-e can be used to pair the stimulator with an IPC ofsmaller or large length, by allowing a patient or doctor to controlwhich contacts are used during the provision of therapy or by havingthese defined or determined as part of a stimulation protocol. Thestimulating array 440 may also consist of one or more alignment loops444 a, 444 b to aid in providing improved alignment with asubcutaneously located IPC. For example, a patient may have permanent ortemporary tattoos placed according to the location of the IPC, such thatthe holes (444 a, 444 b) should be aligned with markers on the patientduring therapy. The figure shows the top side of the stimulating array440, having a backing substrate 446 on which the contacts 442 residewhich can be fabricated using a flexible and electrically non-conductingmaterial such as silicone elastomer, plastic, or nylon. The bottom sidewill simply have the surface contacts 442 a-e. An adhesive surface orpaste can assist in attachment to a subject's skin. The array stimulatormay be configured as a single-use disposable multi-electrode. Electricalconnections 448 run from each contact 442 a-e to a port 449, whichconnects to a plug on cable 422 so that the stimulator 440 can becontrolled and powered from a second accessory port 416 of device 400.The subset of the electrode contracts 442 a-442 e which are used can becontrolled by the device 400, either via manual adjustment, by selectinga particular stimulation protocol, or using a visual interface such as aschematic that is presented on the smartphone device controller 420. Forexample, a user may activate one or more of the electrode contacts bytapping a corresponding virtual electrode shown on a schematic displayedby the smartphone.

In an embodiment a physical landmark, such as at least one bead (e.g., abiocompatible pellet), may be affixed to the skin or implanted under theskin in order to assist with the correct placement of the device 400 ora stimulator 402, 404. The landmark may provide tactile, visual, orother indication which assists in correctly positioning the externalstimulators with respect to at least one implanted IPC.

Controlling and Shaping the eTNS Field

In an embodiment the stimulator array 440 may be coupled to an IPC thatconsists of multiple, electrically-conducting elements that areequally-spaced, or not, with inter-contact 442 a to 442 e distancesalong its length as seen in FIG. 26a . By aligning the one of the endsof electrode contacts 442 a to 442 e with a corresponding edge of thecontacts 454 a to 454 e of the IPC array 452 improved modulation ofneural activity may be achieved. The IPC array 452 may also provideadvantages even when a single TENS stimulation electrode is used. In anembodiment, the IPC may be 3 cm long and may comprise multiple, such astwo, 1.2 cm conductive portions 452 a, 452 b separated by anon-conductive portion. This design may increase the likelihood that asurface stimulator will be correctly positioned and by increasing theprobability that one of its edges approximately aligns with at least oneedge of a conductive portion of the IPC array 452. This may allow theexternal stimulator electrode to be positioned in a less strict mannerwhile still providing stimulation enhancement. In an embodiment, a setof two or more conductive contacts separated by non-conductive substrateare electrically connected (e.g. a conductive element that runs alongthe length of the IPC) so that an electrical field that reaches anysingle contact is transmitted along to other contacts of the array.Improved modulation may also be provided by, for example, independentlymodifying the activating function (e.g., enhanced neural excitation) atone or more locations along a single or multiple nerve(s). Althoughshown wrapped entirely around a nerve, the IPC array can be realized ina cylindrical embodiment that resides adjacent to the nerve, or as ahalf-cuff wrapped partially around the nerve, or otherwise such as alead-type multi-contact electrode array. When the inter-electrodespacing is sufficient, or the stimulation signals are provided atdifferent times, each passive contact 452 a to 452 e can be used toactivate fibers at a different stimulation frequency. In this manner,one or more contacts may be used to promote the generation ofunidirectional nerve action potentials, or to selectively activate onlysmaller diameter fibers. The latter two methods can be achieved byvarious means such as using high frequency stimulation, DC current, orquasitrapezoidal pulses (e.g., Fang Z P and Mortimer J T, IEEE Trans BME1991; Kilgore K M and Bhadra N, Med Eng Biol Comp., 2004).

In an embodiment, the IPC may be configured to selectively activate asubset of fibers or particular nerve fascicle located within a compoundnerve trunk. Examples of such nerves may include the vagus nerve,sciatic nerve, pudendal nerve, posterior tibial nerve, and femoralnerve. This type of spatially selective electrical activation of suchsubsets of nerve fibers is achieved by designing a hollow cylindricalIPC such as in FIG. 26b that consists of a low- or non-conductivesubstrate material 452 (or a conductive material covered in anon-conductive coating), and a strip of high-conductive material 452 falong the length of the IPC. This embodiment will selectively enhancethe excitability of nerve fibers in close proximity to the strip 452 f,while adjacent fibers located closer to the less-, or non-, conductivematerial 452 will exhibit a decreased or no change in excitability. Withprior knowledge of multiple targets (e.g., fascicles within a nervetrunk), multiple conductive strips 452 f may be strategically placedalong one or more IPCs. The conductive strips may also vary in width(around the nerve circumference) and thickness. Again, although thenerve cuff is illustrated in a closed position as a cylinder, it isunderstood that in a common embodiment the cuff is wrapped partially orfully around the nerve during implantation, and the closed cylinder ismerely shown in a simplified manner for purposes of illustration.

In an embodiment, neural enhanced activation may be increased byapplying a non-conductive coating to at least a portion of the externalIPC surface. The extent to which the non-conductive layer covers thesurface may be partial (e.g., one quarter of a cylindrical IPC) orcomplete (entire surface). This effect may be increased by also applyingthis insulating layer to the inner surface of the IPC. In thisembodiment, the area that must remain electrically exposed to thesurrounding environment only includes approximately the circumferentialedges at both ends of the IPC. This method and system of enhancingneural excitability works in conjunction with the preferred design ofexternal (e.g., transcutaneous) stimulating electrodes (FIG. 20a andFIG. 20b ). In FIG. 26c when portions 452 g and 452 f are repeated in aserial manner along the nerve, the IPC may be understood as analternative embodiment of the IPC shown in FIG. 26 a.

An alternative embodiment for shaping the field provided by a stimulatoris to provide stimulation templates such as shown in FIG. 27. Astimulation template provides the advantage of improved nerve modulationby assisting to align an edge of the stimulator and IPC. Even without anIPC, a shaped field may provide improved therapy compared to using alarger field of a whole surface of the stimulator 402,404. Templates canconstrain the stimulator field to allow, for example, shaping of thefield applied to tissue. The template may be shaped according to datathat is obtained in various manners such as visually by measurement,during the implantation operation, by using imaging data, by using datarelated to a physical dimension of the IPC, or by using subject feedbackduring a testing routine that determines the desired area on the surfaceof the patient's skin where stimulation should be provided or avoided(e.g. to avoid certain side effects). As illustrated, a cap template 460can be used to shape the field provided at the cutaneous location byhaving a silhouette 461 or “cut out” that only permits part of thestimulator 402 surface to stimulate a subject's skin. The cap template460 may be attached to the device 400 by means of a cap receivercomponent configured within the device housing. In an alternativeembodiment, a sticker stimulation template 462 may be used with thestimulator surface 404, having an adhesive on one side such that it canbe temporarily affixed to the stimulator surface 404. Rather than usingadhesive, the sticker or cap template may be made out of magneticmaterial so that it can be temporarily affixed and removed from thestimulation surface 404. In a further embodiment a sticker or othertemplate may be affixed to the patient's skin rather than to thestimulation surface.

Regardless of template type, in an embodiment, the stimulation templatesshould have a depth sufficient to allow gel to be applied so that thesilhouette 461 retains the gel while the non-conductive surface of thetemplate remains dry. The silhouette 461 may be further configured witha slight ridge in order to assist in retaining the gel within the shapeof the silhouette 461. Instead of being a “cut out” the cap can beridged such that only a ridged protrudes from the cap surface andengages the skin of the subject. Further, the gel may be similar to theconductive gel often used during ECG recording, or may firmer, such as aconductive paste also used for making EEG recordings. The paste shouldbe sufficiently firm to retain the desired shape of the stimulator.Conductive mediums such as hydrogel, can also be manufactured to fitwithin the silhouette 461 to provide a shaped field. Instead of asilhouette defining a space, the template may have one or moreconductive ridges that protrude to the skin in order to make contact ina more localized manner than the entire surface 402.

IPC Component Designs.

IPCs of the disclosed invention may have many shapes and forms. FIGS.28-30 illustrate embodiments with the understanding that alternativeshapes, dimensions, designs and sizes are possible and may haveadditional features not shown here.

FIG. 28a shows an IPC 500 which is a rod having an outer sheath 502 thatmay be comprised of an electrically non-conductive material orconductive material and inner portion 504 that is conductive. Anadvantage of an embodiment with a non-conductive layer may be thatelectrical current provided by a stimulator would travel through theconductive portion and the conductive edges may serve as 2 distinctpoints. This may enhance activation of the adjacent nerve tissue 12 neareach edge of the IPC. Alternatively, the IPC 500 may be realized withoutcoating 502 as completely conductive. FIG. 28b shows an alternativeembodiment in which the non-conductive outer sheath 502 is partial andonly insulates a majority of the conductive portion 508. In thisembodiment, a conductive lip 510 extends outside of the sheath andstimulates the nerve 12 which is shown oriented perpendicularly to theIPC. In an embodiment this may be a preferred orientation/configurationwhen the purpose of the stimulation is to provide a nerve block in aportion of the nerve 12. However, positioning the IPC lengthwise alongthe nerve is the common configuration for implantation as seen in FIG.28a . Although not shown, all IPCs illustrated are understood to beconfigured with anchor elements such as the suture holes, wings, or thelike. FIG. 28c shows an IPC embodied as a conductive rod 506 (going intoand out of the page, as is the case for FIGS. 28d, 28e, and 29a ). IPC506 may include an anchor element comprised of an elongated arm 530having a first extension 532 a and, optionally, a second extension 532 bthat may aid in positioning and aligning IPC 506 to a target. FIG. 28dshows an IPC configured as an annular rod of conductive mesh 505 with anon-conductive external support surface 502 that serves to decrease thesurface area/density of the IPC. This may serve to increase couplingwith a paired stimulator. FIG. 28e shows an embodiment where the IPC isa hollow conductive cylinder 511 which is wrapped partially around anerve 12, as may be seen with conventional nerve cuff designs. Thecylinder has an opening 512 which may change in size during deformationof the IPC as may occur during implantation under the guidance of asurgeon. Because different IPC lengths can be needed depending upon thesystem configuration, sets of IPCs can comprise IPCs with lengths and orwidths that span a range, for example, lengths from 1 cm to 4 cm, insteps of 0.5 or 1 cm along this range. Larger numbers of more common IPCsizes can be provided in IPC kits, for example, as might be stored instock by a clinic implanting the IPCs as part of tibial nervestimulation treatment. IPCs designs may also allow these to be cut(e.g., in the case of a rod) or folded over/bent (in the case of a thin,foil-like surface design) to adjust IPC length. IPCs can be customized,prior to or during implant surgery. These modifications may be assistedby use of a biocompatible epoxy or sealant, for example, to protectagainst a sharp edge created during this modification.

IPCs will typically be realized as a set of pre-determined lengths forthe general population of OAB patients. In an embodiment related to PTNstimulation in humans, the nerve depth may be approximately 0.8 to 2.5cm deep. A common IPC design may have a length of about 1.5 cm, 350 umthickness, and 3 mm inner diameter. One to 4 lengths could likelyaddress the anatomical diversity across the patient population. Imagingdata may help to select or adjust IPCs design used for a patient. Whenusing IPCs for selective stimulation of PTN nerve branches, PTN shapeand size may be related to the location of the target. More than 1target can be used during therapy. For SAFN nerve branches, tend to runsuperficially, it is likely that one or two sizes of IPC should suffice.

In addition to embodiments shown, it should be understood that an IPCcan be realized as a conductive rod, cylinder, sheet, or wide thread(e.g. 2-4 mm) such as conductive flexible wire suture secured to tissuenear a target nerve, a mesh, a biocompatible conductive gel that is ableto maintain its shape (such as a conductive gel, a flexible, organic,composition of conductive polymers patterned onto slices of hydrogelthat may be surgically implanted near the target nerve or into areceptacle having a pocket for accepting the gel), a plurality ofconductive particles (which may be injected into the target nerve,tissue around target nerve), suitable micro- or nano-based materialsthat allow both biocompatibility and suitable conductivity, as well asdifferent types of conductive nerve cuff electrodes.

FIG. 29a shows two IPCs at locations relative to a nerve target 12arbitrarily located perpendicularly to the IPC lengths. The first IPC500 a has a first length that is different than 500 b in order to allowdifferent external stimulators to differentially stimulate the 2portions of the target during stimulation. FIG. 29b shows an IPC 500 cfabricated such that it coils itself into a hollow cylinder at rest, andselected in size so the inner diameter is equal to or a little largerthan the diameter of the nerve 12. This self-sizing property provided anintimate interface between the IPC and the nerve, and also preventsnerve compression by the IPC following implant (e.g., due to swelling).

FIG. 30a shows an embodiment of an implanted IPC with both a conductiveportion 514 aligned near a target nerve 12 a and a non-conductiveportion 516, that can be realized by a coating that deters electricalenhancing of stimulation field, near a non-target nerve 12 b and thestimulator is located outsize of the page (i.e. the figure is a sizeview). Alternatively, a non-conductive portion can also be realized by acoating that only resides on the underside of the IPC (and thestimulator is located at the top of the page). In the case where the IPCis situated between two nerves where one is the target 12 a, and theother is non-target adjacent nerve 12 b, then the partial shielding mayprevent, or deter, the non-target nerve from being effected by theeTENS. Accordingly a stimulator situated at the top of the page, orpositioned at the angle of the viewer looking into the page, wouldpreferably provide stimulation to nerve target 12 a, while thenon-conductive portion 516 would insulate the field from the non-targettissue area 12 b. The non-conductive portion may also be longer than theconductive portion. At least one securing element 517 such as a suturehole may be provided on the IPC to allow the IPC to be affixed to tissuein the area of nerve. The terminal end of conductive component 514 hasbeen rounded in order to increase the chance of edge alignment with asurface stimulator, wherein alignment constitutes a portion of the twoedges overlapping.

FIG. 30b shows an embodiment of an IPC with at least a first portion 519and second portion 520 of different lengths which are conductive. Thisdesign may increase the chance of enhanced stimulation of a target nerveby increasing the chance that the stimulator will be approximatelyaligned with at least one edge of the conductive portions 519, 520 ofthe IPC. Conductive element 521 may serve to electrically connect thetwo portions 519, 520 that are adjacent the nerve provide additionalenhancement relative to when the element is not provided.

In an embodiment, a stimulus router system (SRS, developed at theUniversity of Alberta) is another example of an implanted device thatachieves a minimally-invasive means of electrically activating theperipheral nervous system. The SRS consists of a metal disk 515 (termedthe ‘pick-up terminal’) that is physically connected via lead wires 524routed to an implanted nerve electrode 526. The pick-up terminal issurgically placed just under the skin surface and ‘captures andre-routes’ electrical pulses applied by an external cutaneously appliedelectrode. Thus, the nerve electrode is powered by means of atranscutaneous coupling mechanism. The system is currently undergoingclinical feasibility testing. This system is essentially identical toconventional nerve stimulation systems, except for the absence of animplanted pulse generator. Instead of an implanted electrical source,this approach utilizes an external stimulation device and at least onesubcutaneous pick-up terminal, which solves the power/control issue atthe cost of other potential issues related to long-term use of the SRS.Further, the effectiveness of the SRS system may be compromised bynon-optimal design of its surface electrode+pick-up terminal couplingmechanism. The methods and systems of the current invention may possiblybe used to improve the SRS system if the pick-up electrode is configuredaccording to the principles disclosed here with respect to pairing oflengths, distances, and edges.

FIG. 30c shows an embodiment of an IPC in which a first conductivecomponent 515 is attached by a flexible conductive element 524 to anelectrode 526 located away from the first conductive component. In onecase the first conductive component 515 serves as a “pick-up” electrodewhich can then relay electrical energy to a more distal location. If thefirst conductive element 515 or electrode 526 is located directly underthe skin then this embodiment may approximate an SRS system. However, asthe pick-up electrode 515 moves away from the skin then the principlesand guidelines of the disclosed invention related to eTENS can be usedto pair the IPC with the stimulator in more efficient manner. Forexample, aligning the edges of a stimulator with the conductivecomponent 515 or electrode 526, or modifying the shape of a stimulatorand a paired conductive component 515 and according to the distancebetween the two system components, as well as other factors, has beendisclosed. By following the principles of the invention the distancebetween the stimulator and SRS conductive component 515 may be madegreater than previously understood while still providing sufficientstimulation of target tissue to achieve therapy.

FIG. 30d shows an embodiment of the IPC in which there are severalportions with a particular attribute 518 a, 518 b, 518 c (e.g. theattribute may be electrically conductive) which are interspersed byportions without that attribute 522 a, 522 b (i.e. non-electricallyconductive). This design can be used either to stimulate differentportions of a nerve or to increase the probability that at least onestimulator edge will align with an edge of a conductive portion in orderto increase coupling according to the principles of the currentinvention. Instead of conductive and non-conductive portions theparticular attribute may be sonically resonant to energy provided by,for example, an ultrasonic transducer (the resonant portions can absorbmore energy when they are driven at a frequency that matches a naturalfrequency, or harmonic, of vibration of the stimulator energy). In anembodiment, since acoustic resonance is a form of mechanical resonance,then any stimulator source that produces energy of a frequency thatmatches the natural frequency of the IPC portion with that particularattribute 518 a, 518 b, 518 c may be used. In an embodiment, theresonant portion of the IPC may be a solid or hollow rod that resonatesat a frequency or harmonic of a stimulation signal provided by thestimulator. In an embodiment, a portion with a particular attribute 518a, 518 b, 518 c is configured to either reflect or absorb light toenhance stimulation of adjacent tissue when an external stimulatorprovides light or laser energy. For example, the portions may bereflective and may be angled such that light energy sent from atransmitter is reflected by the portions onto a specific area of tissueto be stimulated. Additionally, a tube or nerve cuff created from, orhaving at least a portion comprised of, a non-conductive material may beused to insulate non-target nerves from electrical fields while aconductive IPC is used to increase target nerve responsiveness tostimulation. In an embodiment, IPC can be configured with non-conductiveanchor portions (e.g., “shield-flaps”) deployed during implantation toshield non-target tissue from stimulation. The non-conductive substrate516, that surrounds the other components of the IPC may be formed withan outer ring that lends additional rigidity to the IPC in order tocause it to hold its shape if it is bent, or to resist bending, and maybe deployed circumferentially or may also exist along a portion of aside, top, or bottom, of the IPC.

FIG. 31 shows a trans-vascular embodiment of the eTENS system, where anIPC 10 is implanted around a peripheral nerve 12 (e.g., vagus nerve orrenal nerve). A nerve stimulation electrode 533 is inserted into andguided through a blood vessel 534 such that it is in close proximity andin proper alignment with the IPC 10. Electrical stimuli can be deliveredfrom active electrode contacts 531 and/or 536. The electrode 533 may bea lead-type electrode or may be fabricated similar to a vascular stentfor deployment into the vessel. In addition, the electrode 533 may bepowered directly via a lead wire 545, or it may have associatedcircuitry and be powered wirelessly (e.g., RF signal). This embodimentwill enable selective electrical activation of a target nerve 12.

FIG. 32 shows two arrays of surface stimulators 528 a-c and 529 a-b. Thestimulators are located on a patient's back and at least one stimulatoris paired with an implanted IPC located proximate to a spinal nerve. Byactivating disposable or re-usable stimulators 528 a and 529 a thestimulation signal can be modulated by at least IPC located within thepatient. Various spatial patterns of stimulation can be provided by adevice 50, that may be connected to the stimulators and that can becontrolled to stimulate combinations of the stimulators in order toprovide stimulation to a nerve adjacent to the IPC. In an embodiment, byactivating selected pairs of stimulators of the array, such as 528 a and529 a and then 528 a and the upper conductive element of stimulator 529b, the stimulation signals can follow different paths when providingstimulation to at least one IPC in a patient. This increase the chanceof improved alignment between edges of at least one stimulator and anend of the IPC. There are two conductive elements of stimulator 529 b,which reside within single non-conductive support backing structure, andare separated by distance “w”, which may be related to the length orwidth of an IPC. In the embodiment of FIG. 32, each of the stimulatorscan be connected to a device 50/400 which is able to independentlyactivate the stimulators in order to provide spatial or spatial temporalpatterns of stimulation according to a therapy protocol stored in thedevice, or which can be controlled by the patient using manual controlsto selectively activate each stimulator. In the figure an IPC is shownwhich is implanted in a patient at the end of the arrow at point “z”.The IPC could be implanted near a spinal nerve root that is to bestimulated, and the IPC contains a conductive mesh 650, surrounded by anon-conductive supporting structure 652 having a relatively more rigidridge 654 which aids in maintaining the shape of the of IPC.

Clinical Applications

The current invention can be applied in numerous therapies that utilizeany form of tissue stimulation.

The enhanced transcutaneous nerve stimulation methods and systems of thecurrent invention can be used for neuromodulation therapy. Oneembodiment involves electrical stimulation of peripheral nerves that arelocated in relative close proximity to the skin surface. Some examplesof suitable anatomical targets include the occipital nerve, vagus nerve,recurrent laryngeal nerve, sacral spinal nerves, pudendal nerve,posterior tibial nerve, and thoracic/lumbar nerves (lower back). One ormore nerve targets can be used to treat acute/chronic pain, lowerurinary/fecal dysfunction, epilepsy, depression, dysphasia, and otherdisorders as is well known. In some of these therapeutic embodiments, animplantable device may be used to provide or supplement the therapeuticeffects provided by electrical stimulation therapy. For example, OABtherapy can be achieved by an implanted system that stimulates thesacral nerve, and an enhanced nerve stimulation system that stimulatesthe PTN.

The enhanced nerve stimulation system may also be used to treat patientswho are refractory to drug therapy or conventional transcutaneousstimulation therapy. It may also be used in combination with drugtherapy to enhance the therapy or in order to improve the responsivenessof refractory patients.

Embodiments of the present disclosure may be for use with patientshaving specific conditions which are modulated by electricalstimulation. Embodiments may be used with any patient who desires nervemodulation of the brain or body. In addition to use in patients withobstructive sleep apnea, migraine, headaches, hypotension, hypertension,addiction, eating disorders, etc., embodiments may be used to providetreatment in many other areas. Application can include, but not belimited to: brain stimulation (e.g., treatment of Parkinson's, anddepression); stomach muscle stimulation (e.g., gastric pacing);treatment of obesity; back pain; incontinence; overactive bladder;menstrual pain, and/or any other condition that may be affected bytissue modulation.

Embodiments of the disclosed invention can be used in rehabilitationtherapies, such as functional electrical stimulation (e.g., chronicspinal cord injury or stroke), that are used to restore lost or impairedfunction. Examples include rehabilitative strategies involvingelectrical modulation of upper and lower extremity function, trunkstability, and swallowing. For example, in dysphagia, the IPCs of thecurrent invention could be used to prevent aspiration by enabling anexternal stimulator to stimulate muscle(s) in a selective and targetedmanner.

The disclosed invention can also be used for improving conventionalbrain stimulation and deep brain stimulation (DBS) therapy. Oneembodiment involves therapy that is enhanced by surgically implantingone or more IPCs on target tissue in physical proximity to an implantedDBS electrode. The IPC is implanted in a target location to enablesuitable electrical activation of a target area that is deemed difficultto selectively activate by the originally implanted DBS electrode. Theinvention decreases the effect of any sub-optimal placement of, ormigration of, a DBS electrode. The IPC may be less likely to migratebecause it is not connected to a pulse generator. The IPC may be usedwith a DBS stimulator which is operated in any fashion (e.g., bipolarmode or unipolar mode). In the case of bipolar mode, the length of theIPC is preferably the same as the distance between the active DBScontacts. In the case of monopolar stimulation, the dimensions of theIPC (e.g. length and thickness) may be defined as a function of thedistance between the DBS electrode and the IPC. This novel system andmethod can compensate for poor electrode placement that mayalternatively require higher stimulation amplitudes and/or longer pulsewidths. An advantage is less frequent battery replacement and alsodeterring habituation. Reduced stimulation amplitude can also decreasestimulation-evoked side-effects and stimulation of non-target tissue.

Modulation of Drug Delivery

The methods and systems of the current invention can be used in additionto, or as an alternative to, other prior art drug delivery systems suchas for transporting drug carriers across the skin barrier and can beused with micro-needle or subcutaneous drug infusion to guide drugs to atissue target along an intended pathway.

Accordingly, in an embodiment a patient may be selected who isexperiencing a condition, symptom, or state for which the patient wishesto receive treatment. An appropriate drug regimen (e.g. dosage, area ofadministration, etc) is selected for delivery of drug to a tissuetarget. At least one IPC is surgically situated in a target area so thattarget tissue, related to modulation of the condition, is adjacent theIPC. A drug is introduced to the patient by various methods includinginjection of nanoparticles. At least one stimulator may be positionedexternal to the patient to provide stimulation to tissue adjacent to atleast one IPC. The stimulation may be provided according to astimulation regimen which provides the therapy. Results are assessed andtherapy adjusted if needed.

In an embodiment shown in FIG. 23a two stimulators 122 c,d are placedsuch that tissue resides between the stimulators. The unshapedelectrical field 230 a which arises will be wider than the stimulatorsand may be shaped by the heterogeneous and nonlinear impedances ofintervening tissue, including skin tissue. By implanting at least oneIPC 10 a, the electrical pathway between the two stimulators may beshaped (e.g. narrowed). When multiple IPCs are used 10 a,b,c then thesemay serve to form a conductive pathway 236, having a shaped electricalfield 230 b which is biased more along the pathway and may be morenarrow than the unshaped field. In an embodiment one stimulator may beexternal subcutaneous, percutaneous, or implanted, and the 2^(nd)stimulator (can be the same or other type). FIG. 23b shows a secondembodiment using IPCs and compares an unshaped field (top left side offigure) and a shaped field (top right side of figure). As shown a drug234 introduced into the tissue of the patient, may follow a broaderfield than a patient who also has at least one IPC 10 implanted (in thefigure there are 3). When stimulation is provided the drug, in the IPCcondition, is guided in its diffusion along the shaped electrical fieldto the target 232 to provided more directed drug delivery. The bottomportion of the figure shows a monopolar stimulator 122 d and two IPCsconfigure to guide a drug 234 to a target 232, the return electrode islocated distally. In an embodiment, the drug may be contained innano-particles having polarity.

Further Description of the Invention

With respect to treatment provided by IPC selective nerve stimulation, apatient can be selected with a medical condition selected from the groupof, for example, pain, movement disorders, epilepsy, cerebrovasculardiseases, autoimmune diseases, sleep disorders, autonomic disorders,pain, abnormal metabolic states, disorders of the muscular system,cardiovascular disorders, pulmonary disorders, inflammatory disorders,and neuropsychiatric disorders. However, as is evident, a maintherapeutic focus is treatment of urinary bladder and voiding disorders.

The current invention teaches a system and method that can be used toprovide long-term treatment of lower urinary dysfunction related tooveractive bladder (OAB), urinary retention (UR), and detrusorunderactivity (DU). Various symptoms that can be treated related to, forexample, urinary urgency such as failure to be able to postpone the needto urinate; frequency of urination such as the need to urinate at leasteight times per day; urge incontinence such as leakage of urine when onehas the urge to urinate. A primary biological substrate targeted formodulating urinary function is the saphenous nerve, which is a cutaneousbranch of the femoral nerve innervating the lower limb. We will firstdescribe specific characteristics of bladder reflexes that have not beenreported previously by others and that will instruct the methods bywhich OAB therapy can be implemented. Subsequently, we will disclosemultiple embodiments of neuromodulation systems that can allowclinicians to provide effective long-term therapeutic outcomes.

The treatment of “overactive bladder” (OAB) can also refer to treatmentof conditions of urinary incontinence, high urinary frequency andurinary retention conditions, constipation, urinary problems, and/orvarious voiding disorders brought on by nerve damage. Other disorderswhich may be treated are incontinence, urinary pain, erectiledysfunction, idiopathic constipation (as may be achieved by lesseningtime spent on bowel movements and straining effort, increasing frequencyof defecation), interstitial cystitis, high or low frequency of voidingor associated symptoms, symptoms of bladder/pelvic pressure/pain (andmay be accomplished in combination with prudential nerve stimulation),urinary urge incontinence and/or detrusor hyperreflexia. Urinaryregularity may also lead to increased sexual desire. Overactive bladdertreatment may also be used to refer to stimulation which modulatescontraction within targets such as the pelvic floor or “pelvicdiaphragm”. Over time therapy may cause contractions that restore thestrength of the organs and muscles within this system that may be a goalof the therapy. Stimulation induced modulation of pelvic floor,sphincter or other targets can alleviate or eliminate many symptoms ofurinary/faecal disorders. OAB treatment may include treatment of pelvicfloor disorders, such as, bowel disorder including fecal incontinenceand the like, and instead of bladder activity the modulation seeks tomodulate bowel activity or muscle or tissue related to control of fecalmovement, voiding, and containment

FIGS. 13a-c show that across the sample population the PTN, and nervebranches MPN, LPN can yield different responses contributing to thedifferences seen in the average response data. The PTN, MPN, and LPNshow unique, frequency-dependent changes in acute bladder activityrelative to baseline. FIGS. 14a-c and 14 d-f, show that this effectextends to the prolonged responses as well. Further, for acute responsethe MPN seems to be the best target while for prolonged response the LPNis best. This suggests that the best target for quelling symptomsrelated to symptom urgency at the time of stimulation may be differentthan the target for treatment during the night which should followthrough the following day even if stimulation is not provided.

Further, an embodiment of the invention relies upon a newly discoveredbladder-inhibitory reflex pathway that produces results that are uniquefrom those obtained with, for example, posterior tibial nervestimulation, dorsal genital nerve stimulation, pudendal nervestimulation, and sacral spinal nerve stimulation. This can involveelectrical stimulation of the saphenous nerve (SAFN) at a site locatedwithin the lower leg. In contrast to prior art, this involves modulationof sensory nerves that are anatomically derived from the femoral nerveand distributed mainly proximally within the lumbar spinal cord (L2-L4nerve roots). Prior to the results provided herein it was not known, oranticipated, that SAFN stimulation would elicit such a response. Indeed,it is common practice to stimulate the PTN percutaneously, whileignoring the SAFN, although the latter serve as an easier target in somepatients and situations. The novel data disclosed here also support thatlumbar sacral neuromodulation (between L2 and L4), at or near theassociated foramen, may robustly modulate bladder function in mannerthat may be sensitive to characteristics of the stimulation signalincluding frequency and amplitude, and which may be more robust then thecurrently relied upon S2-S4 sacral sites, with S3 being the most common.

The bladder-reflexes evoked by SAFN stimulation were demonstrated usingthe same anesthetized rat bladder model that was used to obtain the dataof FIGS. 13 and 14, and was reviewed in our recently published study forPTN stimulation (Kovacevic and Yoo, 2015). A stimulating bipolar nervecuff electrode was implanted around the SAFN, which was surgicallyisolated just below the level of the knee. The bladder was surgicallyinstrumented with a PE50 catheter and infused continuously(rate=0.08−0.12 ml/min) with saline. Changes in both acute (during10-minutes of SAFN stimulation) and prolonged (10-minutes following SAFNstimulation) bladder responses were compared with a baseline condition(10-minute duration, prior to SAFN stimulation).

FIGS. 34-38 show data obtained using monophasic stimulation pulsesapplied at an amplitude of 25 μA, 200 μs pulse width, and at stimulationfrequencies between 2 Hz and 50 Hz. The different stimulation frequencytrials were applied in a randomized order.

FIG. 34 shows an example typical of bladder inhibition evoked inresponse to 10-minutes of SAFN stimulation. Compared to baseline (toptrace), there is a marked decrease in bladder contraction rate bothduring and after SAFN stimulation (25 μA and 20 Hz). The acute phaseduring stimulation (middle trace), shows a particularly extended bladderfill that begins at 2.5 min and ends at approximately 8 min. Theinhibitory influence of SAFN stimulation persists after stimulation endsand runs into the prolonged period (bottom trace), where extendedinter-contraction intervals, compared to baseline, continue to beobserved.

FIG. 35 shows an example of SAFN stimulation resulting in reflex bladderexcitation. Following a 10-minute stimulation trial, during whichbladder contractions are acutely inhibited, the bladder exhibits anincrease in bladder activity (decreased inter-contraction intervals,compared to baseline) indicative of excitation.

Summary data obtained from experimental study are shown in FIG. 36a,b asthe distribution of three types of bladder responses that were observedin response to SAFN stimulation: inhibitory (>10% decrease in BCR),excitatory (>10% increase in BCR), and neutral (<10% change in BCR).SAFN stimulation applied at 25 μA and 20 Hz resulted in both acute andprolonged bladder inhibition in all 10 experiments (i.e., 100% responserate). SAFN stimulation at 10 Hz also exhibited only inhibition in theacute condition, and predominantly bladder-inhibitory responses inprolonged time periods. Although the response rates of acutebladder-inhibitory responses were notably lower at frequencies above andbelow the range of 10-20 Hz, it is noted that the prolongedbladder-inhibitory responses between 2 Hz and 10 Hz were relativelyconsistent (63% to 78% response rates).

While the data indicate that MPN and LPN stimulation at 10 Hz can,respectively, achieve acute and prolonged bladder inhibition in 100% ofrats (FIGS. 14b,14f ), a single neural target/stimulation protocol (SAFNstimulation at 20 Hz) achieved 100% response both for acute andprolonged bladder inhibition. Further, the SAFN stimulation achievedthese inhibitory responses at approximately 20% of the stimulationamplitude required for MPN/LPN stimulation. This indicates that the SAFNwould be a good, or at least sensitive, candidate for a stimulationprotocol. The reduced signal amplitude has benefits of reducing powerrequirements of an implanted device and the potential for lessside-effects, such as pain, from unintentional stimulation of non-targettissue.

In addition to inhibition, bladder-excitatory responses occurred atstimulation frequencies above and below the 10-20 Hz range in the acuteresponse, and also at 10 Hz in the prolonged response. While theexcitatory bladder reflex was observed in 13% to 29% of experiments (for5 to 50 Hz stimulation rates), 2 Hz stimulation showed an incidence of38% in the acute response. The 2 Hz bladder-excitatory reflex suggests apotential treatment for voiding disorders, such as UR and/or DU, wherebya stimulation protocol of a neurostimulation system uses this frequencyrange (e.g., +/−1 Hz) for at least a SAFN target to produce bladderexcitation. This reflex was also observed in response to 2 Hzstimulation of the LPN. Post-stimulation excitation was also evoked byelectrical stimulation of the PTN, MPN in FIGS. 13a-13c . Additionally,a stimulation protocol of a neurostimulation system may use higherfrequency stimulation in the 50 Hz range, or higher, for at least one ofthe PTN, LPN, or SAFN to produce an excitatory bladder response. Stimuliin the 2 Hz range and 50 Hz range could be used for the LPN and SAFN,and the site and stimulation signal parameters that elicit the largestacute and/or prolonged excitatory response can be selected forsubsequent therapy in treatment of UR/DU. In addition to theseperipheral targets, one or more of their corresponding spinal nerveroots may be selected to be therapy targets that are activated by astimulation protocol of a spinal stimulation system during treatment.

FIG. 37 shows summary of the mean percent decrease in BCR (both acuteand prolonged bladder inhibition) averaged over 10 experiments as afunction of stimulation frequency rate and does not include (in the meancalculation) any response which increased BCR. Despite the different“inhibitory” response rates to SAFN stimulation shown in FIGS. 36a,b itwas found that the magnitudes of the inhibitory responses (forstimulations that evoked decrements in BCR) are robust at allfrequencies. This finding suggests that there are other effectivestimulation parameters available to patients who may not tolerate orrespond to 20 Hz SAFN stimulation. As suggested by the prolongedresponse rates in FIG. 36b , it may be that 43% to 78% of a humanpopulation will also respond well (>10% reduction in BRC) to frequenciesother than 20 Hz.

A similar examination of the bladder-excitatory responses of FIG. 38shows that the magnitude of increased bladder activity (increase inbladder contraction rate) is also robust in a small portion of patients,particularly at lower stimulation frequencies (2 Hz and 5 Hz). Theobservation of an acute excitatory response (e.g., 2 Hz at 25 μA) evokedby SAFN stimulation suggests the clinical use of this stimulationsignal/target for providing, at least to some individuals, a rapid(on-demand, or in response to a detected event) method of initiatingand/or sustaining a bladder void, such that a sufficiently low residualbladder volume is achieved (e.g., less than 50 ml). In an embodiment,this bladder-excitatory reflex can be induced by stimulation provided bya stimulation protocol to reduce the time needed for a patient with URor DU to complete the process of bladder emptying (e.g., <1-2 minduration). For example, nerve targets and stimulation signals areselected in stimulation protocols to provide rehabilitation therapyaimed to re-establish normal activity in the bladder system over time.In another example, by achieving more efficient bladder emptying thepatient can reduce the duration, amplitude, or provision of inhibitorystimulation subsequently needed for the next urinary cycle.

The data in FIGS. 36a,b indicate that there are some rats (and possiblyhuman patients) that respond differently (are less responsive) tofrequencies outside of the 10-20 Hz range, compared to frequencieswithin that range. If 20 Hz should not be used in a particular patientat the SAFN site, for whatever reason, then as further supported by thedata of FIG. 37, stimulation may be able to achieve the same therapeuticoutcomes as those who respond at 10-20 Hz. Accordingly, thesefrequencies can be defined as a fallback stimulation protocol for somepatients who do not respond to 10-20 Hz.

Although SAFN stimulation achieved robust bladder inhibition at very lowstimulation amplitudes (25 μA, near the sensory threshold), the effectof increasing the stimulation amplitude was also investigated at 10 Hz.FIG. 39, shows very strong bladder inhibition both during and followingSAFN stimulation (amplitude=50 μA). In this example, any ongoing bladderactivity during SAFN stimulation (circled activity in middle trace)disappears after approximately 5 minutes of stimulation. Beyond thistime point, the bladder fills with very high compliance as shown bycontinuous elevated baseline bladder pressure, while the saline infusedinto the bladder passively leaks through the urethral meatus as randomdrops. As shown in FIG. 39 (bottom panel), this state of bladderatonicity (i.e., underactivity) persists well beyond the 10 minuteduration of SAFN stimulation.

FIG. 40 shows the incidence of inhibition evoked by SAFN stimulation,and shows that increasing the stimulation amplitude, while maintainingthe frequency at 10 Hz, results in an increase in the number of ratsthat achieve acute bladder inhibition (top panel). Compared to the 90%response rate exhibited by SAFN at 25 μA, all rats respond to 10 Hzstimulation when the amplitude is increased to 100 μA (i.e., 100%response rate). This data suggests that, in addition to 20 Hz SAFNstimulation at 25 μA, higher amplitude SAFN stimulation at 10 Hz canalso provide a reliable means of rapidly inhibiting the urinary bladder:higher stimulation amplitude can change the bladder response evoked by aselected stimulation frequency. Increasing the stimulation amplitudealso affected the prolonged response evoked by SAFN stimulation at 10Hz. As shown in the bottom panel, stimulation trials applied at largerstimulation amplitudes resulted in the loss of any post-stimulusexcitation of bladder function. Lastly, we note a marginal increase inthe bladder-inhibitory response rate between stimulation amplitudes of25 μA and 50 μA: response rate increased from 77% to 80% (although thisis likely noise).

A higher stimulation signal amplitude may be more likely to causeunwanted side effects such as pain, or adjacent nerve stimulation.However, the results suggest that the amplitude may be used as part of astimulation protocol to modulate the amount of either excitation orinhibition of bladder activity that results from stimulation. For agiven stimulation frequency, increasing the stimulation amplitude maycause the functional state of the urinary bladder to shift, for example,from one that is excitatory to one that is inhibitory.

The physiological evidence of an acute bladder-excitatory bladderresponse (or at least increased BCR) evoked, for example, by 2 Hz SAFNstimulation supports an embodiment of a neurostimulation system with astimulation protocol for assistance in providing acute bladder emptyingin patients diagnosed with UR or DU. A patient could select astimulation program to initiate a “bladder voiding” protocol, eitherprior to (e.g., several minutes) or at the start of a void. Preferably,this acute therapy could be delivered by eTENS or a fully implantednerve stimulation device.

Conversely, the evidence of an acute bladder-inhibitory bladder responseevoked, for example, by 10 Hz SAFN stimulation (see FIG. 36a and FIG.38) suggests an embodiment in which a neurostimulation system uses astimulation protocol for immediate amelioration of OAB symptoms. Thiscould benefit patients with sudden onset of strong urinary urgency thatcould result in an incontinence episode. eTENS is well-suited for PTNtherapy and perhaps even better for SAFN stimulation, which hassuperficial branches, more superficial to the patient's skin.

A further examination of the magnitude of changes in bladder function ispresented in FIG. 41. The top panel shows the magnitude of acutebladder-inhibitory responses did not change much with increasedstimulation amplitude. However, the prolonged bladder-inhibitoryresponse showed a notable increase in the bladder-inhibitory responsefor the two higher amplitudes. The bottom panel of FIG. 41 reflect thefindings in FIG. 40, where increased amplitude of SAFN stimulationabolishes the excitatory bladder response.

The data presented in FIG. 40 and FIG. 41, taken together, provideevidence that increasing the stimulation amplitude of SAFN stimulation(1) improves the response rate of the acute bladder-inhibitory reflex(100% at 100 μA), and (2) increases the magnitude the prolongedbladder-inhibitory reflex (87% increase between 25 μA and 50 μA). Theseresults support that, in addition to the stimulation frequency as shownin FIG. 35 through FIG. 39, the pulse amplitude can also be adjusted forthe stimulation protocol to achieve effective treatment of OAB.Selection or adjustment of stimulation signal amplitude can serve tochange the effect of therapy from inhibitory to excitatory, and/orprovide different amounts of bladder modulation, at least in the case ofSAFN stimulation.

The results also suggest that, for SAFN stimulation, a medium (or high)amplitude signal may provide a better therapy than a low amplitudesignal (e.g., at sensory threshold), as long as it can be well toleratedby patients. In one embodiment, the signal provided by a implantedstimulator is increased until the subject experiences an unwanted sideeffect, and then the signal is reduced a given percentage, such as to80% of the signal that produced the unwanted sensation 9 (e.g. tinglingor pain). In another embodiment the amplitude of the signal for SAFNstimulation is between 50 and 100 μA. Since the threshold may varysignificantly from one patient to another it is likely best to set theamplitude individually for each patient. In an embodiment, a standardtherapy will provide SAFN stimulation at 20 Hz using stimulation signalswith amplitudes that the patient can tolerate (start at 25 uA). Thepatient response will be assessed by increasing in steps of, forexample, 10 or 25 uA. If a patient cannot tolerate 20 Hz SAFNstimulation, or if this does not provide the desired inhibitorymodulation of bladder activity, then a 10 Hz signal can be selected. Ifneither 20 Hz nor 10 Hz signals provide therapeutic benefit afterseveral sessions, then the stimulation amplitude can be increased forthe 10 Hz signal, or a different stimulation frequency can be selected,potentially between 2 Hz and 50 Hz. Further, alternating stimulationparameters, even during a single stimulation session, may beadvantageous. For example, some patients may not be able to tolerateconstant frequency and/or amplitude stimulation, and as a consequencetime-varying stimulation patterns (variable frequency, amplitude, pulsewidth, etc) may be selected to improve overall therapeutic effectivenessand patient compliance.

If SAFN stimulation does not work, then an alternative therapy may bemore successful, such as PTN, LPN or MPN stimulation provided by eitheran implantable stimulator or eTENS system. Accordingly, in a treatmentmethod the site of stimulation may be adjusted to a different targetnerve if stimulation of the first target nerve does not provide therapy.Additionally, in an embodiment both the first and second target nervemay be stimulated concurrently, or sequentially, by the stimulationprotocol. If none of these options prove effective, then the cliniciancan suggest moving to a spinal target, and a test period usingpercutaneous spinal nerve stimulation with temporary leads (e.g., ofL2-l4 nerve roots). If effective, the patient is surgically implantedwith a lumbar nerve stimulation system that may, or may not alsostimulate a sacral root such as S3.

Several clinical embodiments of the invention can serve to provideeffective treatment of OAB and its symptoms. The therapy can bedelivered by electrical nerve stimulation applied in the peripheral orcentral nervous systems (e.g. spinal) and can be achieved by apercutaneous needle electrode, conventional implantable pulse generator(IPG), a BION (active or passive model), eTENS, conventional TENS,magnetic stimulation, ultrasound stimulation or any other clinicallyviable method of neural activation. In one embodiment, the therapy caninvolve finite duration (e.g. 30-60 minutes) stimulation that isrepeated on a pre-determined time schedule (e.g., daily, weekly, etc).Depending on the nerve stimulation technology used to activate targets,such as SAFN afferents, therapy can be provided in a clinical setting,or as an at-home system, or other manner. Based on the presented data ofFIGS. 34-41, SAFN stimulation delivered at a frequency of 20 Hz, pulseduration of 200 μs, and stimulation amplitude at approximately 1× to 2×the sensory threshold of a subject (e.g., 25 μA), and below a sensationthat causes discomfort, should provide improved suppression of OABsymptoms and preferable response rates among many patients. The optionsof modifying the stimulation frequency (between 2 Hz and 50 Hz), thestimulation amplitude, and even the site of stimulation, providesfurther tools for the clinician to program a “customized stimulationprofile” for a stimulation protocol that will improve long-termcompliance to, for example, SAFN therapy. Changes in the stimulationwaveform (e.g., sinusoidal) and pulse width may also contribute toachieving effective therapy.

Some side effects, such as potential issues associated withparesthesia—typically encountered during sensory nerve stimulation—maybe circumvented by using stimulation protocols with time-varyingparadigms of stimulation in the case of the SAFN and other targetsdisclosed herein. This may include, for example, periodic increases anddecreases in stimulation amplitude, pulse width, frequency, waveform, orany other relevant parameter. For example, rather than turning thestimulation signal off, it may be reduced by 30-50% in terms of durationor amplitude over a selected interval. These changes may occur overperiods of milliseconds, seconds, minutes, or hours. Moreover, one ormore of these parameters may be varied simultaneously or at differentpre-determined times. These changes can be controlled by the stimulationprotocol of a device 50.

In an embodiment, SAFN stimulation therapy (e.g., 30 minutes of nervestimulation) may be provided at random times throughout the urinarycycle, or it may be prescribed by the clinician to be delivered atspecific points within the cycle. For example, SAFN therapy for treatingOAB may be most effective immediately prior to or following a void, theearly phase of the bladder storage period (up to 50% of bladdercapacity), the latter phase of the bladder storage period (between 50%and 100% of bladder capacity), or during the voiding period. The therapycan be provided at points in the cycle that are identified automaticallyby the therapy protocol of an implanted or external device, or by thepatient. For example, a patient may use an external device 72 toindicate this to an implanted device 110 or may simply operate anexternal neurostimulator device to provide therapy.

Stimulation Protocol Assessment and Adjustment.

The stimulation parameters may be modified to improve the therapeuticeffect, patient comfort, or both of a therapy such as SAFN therapy. Theassessment of stimulation 628 depicted in FIG. 52 can occur for acutechanges (approximately during stimulation) or can occur for prolonged“post stimulation” changes, which can persist over minutes, hours, ordays after a stimulation trial is provided to the patient. The measuredchange that is assessed may be physiological such as bladder pressure(obtained by one or more sensors 634 as seen in FIG. 53a ) or maximumbladder capacity, or may be assessed using patient symptoms. Theassessment may utilize a stimulation protocol that provides at least twodifferent types of stimulation protocols (e.g., to 2 different sites orusing different stimulation signals) and the patients response can beassessed in order to adjust or select the subsequent stimulation 630 ofFIG. 52.

Additionally, referring to FIG. 52, parameter values that guide the twodifferent stimulation protocols can be implemented 626 and/or assessed628 independently, one for acute treatment and one for a chronic (orprolonged post-stimulation) therapy regimen. The acute treatment mayoccur in addition to, or instead of, the therapy program implemented forchronic therapy. For example, periodic low amplitude MPN may be best forcontinuous treatment in a particular patient (chronic paradigm), but ifthere is an acute event (e.g., increased sense of bladder urgency), andthe patient wishes rapid and supplemental therapy (e.g., to obtainbetter symptom relief), an acute stimulation protocol can be selectedfor addressing the immediate symptom(s).

In one embodiment, assessment can occur at an interval afterimplantation and a patient may be asked to drink an amount of water(e.g. 2-5 glasses) that serves as a stressor. The patient then waitsuntil an urge to urinate occurs. An assessment period may provide atleast 1 stimulation signal for at least 2 different targets and thesubject can be asked both during stimulation and after (prolongedeffect), to rate “subjective urge” both during and after the stimulationprotocol. This protocol can be used to assess at least 2 stimulationsites/signals. In an embodiment of an assessment protocol, thestimulation frequency for a given target is increased from 2 Hz to 25 or50 Hz, in 3 or 4 Hz steps. Each setting can last for a given duration(such as 1 minute) and the subject can provide verbal or otherindication of urge. This can be repeated for a second candidate site.The most effective stimulation protocol(s) identified by thesepost-surgical tests can be used subsequently during therapy.

Selective Nerve Branch Stimulation.

The prior art has not previously shown any clinically significantdifferences between stimulation of the MPN, LPN, and PTN targets fortreating lower urinary tract dysfunction, such as OAB. A plausiblereason for attempting stimulating the LPN or MPN, rather than the PTN,may be that these targets could decrease levels of pain or discomfort ofsome subjects by either minimizing the total number of PTN fibers thatcontribute to these unwanted sensations or by avoiding to concomitantactivation of non-targeted nerve fibers within the ankle region (e.g.,sural nerve). Another reason is that electrical activation of PTNbranches within the foot may be achieved with TENS and thus could beseen as easier to implement clinically than percutaneous PTNstimulation. However, the data presented herein suggest the clinicaladvantage that electrical stimulation of these different neural targetsmay lead to different levels of therapeutic efficacy in OAB patients:patients who are refractory to one stimulation site may respond verydifferently to another target nerve. Accordingly, an implantableneurostimulator may be improved by allowing selective activation of morethan one of these neural targets (PTN, LPN, MPN and SAFN). An example isa patient where stimulation of the PTN trunk does not provide therapybenefit, while one of the PTN nerve branches does provide the desiredtherapy.

The novel results shown here support that electrical stimulation of thePTN, LPN, MPN, and SAFN can independently and uniquely provide (or atleast differ in efficacy with respect to) control of bladderfunction/continence, and by association, other functional targets withinthe abdominal and/or pelvic viscera, e.g. bladder, urethral sphincter,intestines, the uterus (in females), rectum, and anal sphincter. Asystem that provides selective nerve stimulation to any one of theseperipheral nerve targets, or to one or more of their correspondingspinal roots, can be used to achieve unique and effective therapeuticresults. Further, therapy response may vary at a nerve target in afrequency-dependent and/or amplitude dependent manner. Additionally,providing distinct stimulation input(s) in order to differentially andindependently modulate at least one of at least two of these nervetargets may itself achieve therapeutic outcomes, or even augment thetherapeutic effectiveness of electrically stimulating a single neuraltarget such as the PTN. Delivering electrical neuromodulation therapy byalternating the stimulation site over time may offer advantages such asdecreasing the risk of interaction effects (e.g., as may occur when thenet stimulation results in a decrease in bladder modulationeffectiveness compared to that obtained when only one of the nervetargets is stimulated) and decreasing demands on a power source such asa battery when two sites are stimulated simultaneously. Alternatingnerve targets may also serve to decrease the risk of adaptive,habituation, or compensatory processes related to long term nervestimulation of a single target.

The data presented in, for example, in FIGS. 13, 14, 36, and 38, showthat the therapeutic efficacy obtained by stimulating a first nervetarget of either LPN, MPN, SAFN or PTN may not be effective, or may beless effective, than stimulating an alternative nerve target. Systemswhich are configured to stimulate a second target in the case that afirst target does not meet a therapy criterion can provide improvedbenefit. In order to assess the candidate targets, a method can includeimplanting 30 at least one stimulator electrode which stimulates atleast two of a plurality of nerve targets at least one of sequentially,concurrently, and independently. In an embodiment an assessment protocol34 operate using an evaluation protocol, such as stimulating a firsttarget at two or more frequencies or rates such as 5, 10, 15, 20, 25,and 30 Hz. The therapy may be assessed during stimulation or after aninterval such as minutes, days, weeks, or months after each of at leasttwo of these frequencies have been used to provide stimulation of apatient. Additionally, assessment 34 can then repeated for the secondtarget. The results of stimulating the at least two targets can then beassessed for measures such as urgency and frequency of daily voiding. Inan embodiment, when the frequencies of the signals have been selected(e.g., using the 2 protocols and sites that produced the best resultsfor the best and second best target independently), a further step isaccomplished in which each of the targets are stimulated alone and thenboth targets are stimulated in combination. The stimulation protocol canthen provide nerve stimulation 626 that resulted in the greatesttherapeutic response, either at one or both stimulation sites.Alternatively, if only one site produced therapy, then the second sitemay not be used. Assessment of therapeutic efficacy can be assessed forthe different stimulation signals used in the protocols either duringstimulation or after stimulation. When assessment occurs duringstimulation the assessment may include, for example, measuring thesubjective ratings of a subject or can be data sensed by a sensor. Afterstimulation, assessment may include data recorded in a bladder diary oronline database.

In an embodiment, an implantable system for stimulation of at least onenerve branch of the PTN may occur without a stimulator implanted neartarget a site within the foot of a patient that is distal to the talus.Although the PTN branches become physically discrete within the footdistally, using this region even with an IPC may be uncomfortable, maybe prone to component migration, and may increase the risk of damage andcomplications to the system components and surrounding tissue due topressure and sheer. Additionally, tunneling lead wires from aneurostimulator located near the ankle to locations in the foot may beprone to problems such as lead dislodgement and fracture. Surgicallyaccessing each PTN nerve branch (e.g. at or slightly below the level ofthe medial malleolus location) and providing selective branchstimulation within this single anatomical area may be more suitable thanrelying upon stimulation sites more distally within the foot. The PTNbranches may be surgically accessed using a first nerve cuff tostimulate the LPN and a second nerve cuff to stimulate then MPN, ordifferent contacts of a multi-contact nerve cuff, lead, or electrodearray 662 may be used near the site where the PTN divides into thesebranches. Alternatively, an electrode lead configured with at least oneelectrically conductive “tooth” or wedge, can be conveniently used tostimulate at least one nerve branch of the PTN, when implanted, forexample, by a neurosurgeon to avoid excessive damage of the nervetissue. Multiple teeth can be used to selectively stimulate more thanone PTN branch. For example, multiple teeth can be provided usingdevices such as the longitudinal intrafascicular electrode (LIFE).Alternatively, although more problematic (as stated above), one or moretarget nerve branches in the foot itself may also be used to provideselective PTN nerve branch stimulation with at least one implantablestimulator.

A main advantage of the invention, is to provide stimulation protocolswhich rely upon stimulating one of the PTN nerve branches, rather thanthe full PTN trunk, since the novel nerve branch data provided hereinshowed that for some patients, at least for a given frequency andamplitude (and set of 1 or more electrode contacts used to provide thestimulation to a target), selective nerve branch stimulation may producemore effective acute or prolonged modulation of bladder activity thanfull PTN trunk stimulation. The disclosed systems and methods may alsobe designed to realize stimulation protocols that are based upon afinding that, at least for some animals, a stimulation signal can causeeither excitation or inhibition based upon at least one of: stimulationfrequency, stimulation amplitude, and nerve target. Particular nervebranches, or associated spinal roots, may produce bladder excitation orinhibition dependent upon one or more stimulation parameters. Althoughthe data disclosed herein was derived from electrical nerve stimulationat distal sites of the peripheral nervous system, the invention alsosupports novel stimulation paradigms for spinal targets which correspondto these peripheral pathways and which may produce results well alignedwith those shown herein. Furthermore, just as LPN stimulation may not beeffective in a patient, and a different target such as the MPN canprovide better therapy when selectively stimulated, this may be true atspinal stimulation locations. For both peripheral, or spinal, ormixtures of the two, combination therapy of at least two targets mayprovide better therapy than a single site.

A system may provide independent stimulation to at least 2 nervetargets, although only one may be relied upon if, after implantation,only one is found to provide the benefit to the patient. In someinstances, combination LPN and MPN stimulation may not provide therapybenefit, or may provide worse benefit, then when the same stimulationfrequency is used to modulate both targets. In an embodiment, a methodused by a stimulation protocol of an implanted neurostimulator has afirst step of providing and assessing stimulation of a first target toderive successful stimulation parameters (e.g., frequency, amplitude)for producing intended bladder modulation. This step is then repeatedfor a second target candidate. The two targets may then be used togetherto provide improved therapy. However, therapy should also be assessedwhen combining targets using the successful stimulation signals, toensure that the combined stimulation (e.g., provided simultaneously,periodically, or in an alternating manner, etc) provides improvedtherapeutic effects to either stimulation provided alone. Additionally,in the course of therapy, if sufficient therapeutic benefit is notsustained, then the second target can be added or removed (if alreadypresent) from the stimulation protocol.

Results presented herein suggest that the PTN and SAFN stimulationrelate to at least partially different bladder modulationmechanisms/pathways. For example, significantly lower stimulationamplitudes are effective for modulating bladder activity using the SAFNcompared to the PTN, and its branches suggesting a different bladderreflex mechanism. Differences found at peripheral target sites suggestthat the corresponding spinal nerve roots may also modulate bladderactivity through different central and peripheral reflex systems.Accordingly, L2, L3 and L4 (SAFN nerve roots) may provide differentsensory inputs from the commonly used S3 for modulating bladderfunction. Further, this characteristic can extend to the full set ofspinal roots including L5 to S4 (i.e., tibial nerve roots). It followsthat stimulation of L2 and/or L3, and/or L4 instead of, or incombination with, S3, or other tibial nerve roots, may improve therapyin some patients with pelvic floor disorders such as overactive bladderby treating the disorder using different mechanisms. Such modulation maysimilarly be sensitive to stimulation signal characteristics—includingat least the stimulation frequency and amplitude—that may provide foreither inhibition or excitation of bladder activity. It is likely thatthe SAFN produces bladder modulatory effects primarily via L3 and L4nerve roots, and to a lesser extent via the surrounding L2 and L5 roots.Electrical activation of more than one spinal nerve root may be requiredto produce therapeutic efficacy that is similar to that produced by theperipheral SAFN stimulation in the lower leg, which activates multiplespinal targets. In an embodiment, a neurostimulator is configured with astimulation protocol that provides a first stimulation signal to a firstelectrode stimulator to stimulate at least one of an L3 or L4 nervespinal root target and a second stimulation signal to a second electrodeto stimulate an S3 spinal root nerve target.

The ability of stimulation signals with different amplitude andfrequency combinations to cause either bladder excitation or inhibitionat the same stimulation site may extend to other spinal nerve rootstimulation sites than those disclosed above, such targets selectedbetween T1-S4. The SAFN, stimulated peripherally in the lower leg, hasthus far been shown to be the most effective site of stimulation formodulating bladder activity, suggesting the L3-L4 roots may be moresensitive as well. The LPN data at 2 Hz and 50 Hz show the strongestexcitation acute and prolonged response. The PTN stimulation also showsthis reflex, but this seems to be mediated primarily by the LPN:selective stimulation of LPN may be more effective in producingexcitation.

An embodiment of the stimulation protocol may be based upon LPNstimulation results that may correspond to a spinal nerve set 3(including S1,S2 roots), and MPN stimulation results that may correspondto spinal nerve set 4 (including L4,L5 roots, see Atlas of HumanAnatomy, Frank Netter). These two sets of spinal nerve roots may be usedin a stimulation protocol that is configured to stimulate at least afirst nerve target selected from set 3 and a second nerve targetselected from set 4 in order to take advantage of the differentialresponses shown in the data presented herein for LPN and MPNstimulation. For example, S1 and S2 may be more useful in providingbladder excitation than other targets, especially with stimulationfrequencies in the 2 and 50 Hz range, since this was seen for LPN.

Since LPN was found to be effective in the rat data results presentedherein, indicates that the sural nerve (and its cutaneous nerve brancheswith corresponding L5, S1, S2 spinal nerves) may also be an effectiveperipheral target since both the LPN and sural nerve terminate in theS1, S2 spinal roots. Likewise, the sciatic nerve, femoral nerve, andlateral cutaneous femoral nerve branches may also be appropriate due tothe origin of their spinal roots. It is a novel feature of the inventionto selectively stimulate individual nerve branches, since selectiveactivation of peripheral nerve branches, especially those of the lowerlimb, such as the LPN and MPN have shown to produce different/betterresults than stimulation of the whole nerve trunk. Further, since two ormore branches may produce different results, stimulation protocols andrelated assessment should incorporate this finding into stimulationprotocols that treat separate nerve branches as different targetcandidates.

In an embodiment an assessment procedure is provided before the start oftherapeutic stimulation of the patient. In the assessment procedure, asubject is stimulated using at least 2 temporary stimulation leads. Theleads are configured to stimulate at least 2 nerve targets selected tobe from L2 to S5, where a first is implanted to stimulate a site inL2-L4, and the second to stimulate at a site at L5-s5. Both during andafter stimulation is provided, sensed data and/or subjective evaluationby the patient, may be obtained from the patient in order to assess theacute and/or prolonged effect on bladder function and related symptoms.During treatment one or more targets and stimulation signals whichprovided for improved therapy results during the assessment procedureare selected for subsequent therapy provided by a treatment protocol.

In an embodiment, a system and method for treating OAB comprises drugtherapy such as transurethral injection of Botox into the bladder wall629, intrathecal injection or oral consumption. The drug may be providedor adjusted in order to enable a broader range of nerve stimulationparameters to provide effective bladder modulation and also decreaseunwanted side-effects elicited by nerve stimulation. For example,providing a drug may allow therapy benefit to be obtained at a lowerlevel of stimulation. Adjustments to drug may involve, for example, oraldosage, volume per injection, drug concentration, and number oflocations of injections. Additionally, the provision of electricalstimulation can decrease the amount of drug needed and the associatedside-effects of the drug therapy used to treat overactive bladder. Thecombination of electrical and drug therapy may result in a synergistictherapeutic outcome that requires either reduced drug use, or reducedamplitude of electrical energy during stimulation, or both.

Multi-Modal Stimulation.

Nerve stimulation can rely upon stimulation signals of variousmodalities. Examples of ultrasound transducers which can be used todeliver ultrasound to stimulate tissue are disclosed in U.S. PatentApplication Publications 20150025422 and 20140094720 (both entitled“Methods and Devices for Modulating Cellular Activity Using Ultrasound”)as well as 20110213200 (“Orgasmatron via deep-brain neuromodulation”).The prior art does not use an implanted passive element to absorb,reflect, or focus the stimulation energy in any manner. There is noprovision of an IPC designed to be resonant with the supplied energy.U.S. Patent Application Publications 20140316499 and 20130096656 (bothentitled “Neurostimulator”) and 20100130867 (“Ultrasound frequencyresonant dipole for medical use”) disclose materials with beneficialproperties and configurations that may be used to convert sound toelectrical stimulation. These patent publications are incorporatedherein by reference in their entirety for all purposes. The use ofabsorbing or reflecting sound in order to focus modulation energy withinlocal tissue, such as to produce peripheral nerve stimulation in thetreatment of OAB according to the principles of the current invention isnot disclosed by the aforementioned prior art. The IPC may be selectedto be made from a material including polyvinylidene fluoride, ceramic,crystal metal quartz. The IPC can have a biocompatible coating that iseffectively transparent to ultrasound. When two IPCs are activatedseparately, the first and second materials should have resonantfrequencies (and other relevant sound characteristics related toabsorbing or reflecting sound) sufficiently dissimilar that when thefirst and second IPCs are exposed to a signal having a frequency similarto the resonant frequency of the first IPC, the second IPC does notcreate a significant vibration. Although the prior art suggestsfrequencies of ultrasound that are suitable to stimulate tissue, otherfrequencies of sound or vibration, which are sufficiently lower may alsobe useful in this application. The size, shape, and density of the IPCcan be adjusted so that the IPC is maximally activated by the incomingenergy.

Additional Stimulator Embodiments.

The methods and systems disclosed here may utilize a number ofalternative embodiments to provide selective nerve stimulation. Becausethe nerve targets in the lower leg may be very near each other variousembodiments may provide advantages in providing selective stimulationaccording to the principles of the disclosed invention. In FIG. 42 toFIG. 51, the relative size, position, and shape of the nerve and thesystem components are not meant to be limiting and are presented forillustration purposes only. FIG. 42 shows several system componentswhich can be used to implement various strategies for providingselective nerve stimulation. In an embodiment stimulator includes aflexible annular, or semi-annular (i.e. concave) nerve cuff comprising atop side 580 a and a bottom side 580 b with a non-conductive wall therebetween, having an inner wall surface 582 a and an outer wall surface582 b. When multiple electrode contacts 586 are disposed on the innerwall 582 a, such may be positioned near a target nerve or nervesfascicles within a nerve trunk, for example, MPN and LPN duringimplantation (which may or may not be visible at the level near themedial malleolus). The conductive pathways 584 may be insulated and cansupply electrical power to the contacts 586. Alternatively, if thecontacts 586 are not provided then the conductive pathways may not beinsulated (or may be partially insulated) in order to serve as electrodecontacts themselves. Each conductive pathway 584 may contain multipleconductive conduits and can independently operate more than the set oftwo contacts 586 shown. Although physical proximity of an electrodecontact 586 to a target nerve may be straightforward, and placementduring implantation allows target nerve branches to be stimulateddirectly by contacts, in another embodiment the stimulation protocolactivates different patterns of the electrical contacts 586 in order tosteer the electrical field to a target a selected nerve or a nervebranch within the nerve trunk (e.g., to target LPN within the PTN).Although current steering (spatial biasing of the electrical field)using an electrode array is well known, the benefit of stimulating anerve selected branch rather than the entire PTN was not known prior tothe data presented here. U.S. Pat. No. 8,509,920 entitled “Electrodearrangements for medical lead” discloses a system that may allow forthis feature and is incorporated by reference herein. The electricalsignals can be transmitted to the electrical contacts 586 and pathways584 by means of a multi-stranded cable 588 that communicates stimulationsignals from a neurostimulator. Alternatively, microcircuitry may beprovided at the junction of the bottom side 580 b and the stranded cable588 to allow for multiplexing and signal routing. A signal router andpaths between the stranded cable 588 and the conductive pathways 584 arenot shown in FIG. 42 for purposes of clarity. Additionally, the nervecuff may be designed to be more fully closed during implantation but isshown in the current form for illustration. In an embodiment, only oneor two electrode contacts are used and each of these may be realized toreside within a large area of the cuff, such as extending the entirelength, the entire width, or along a large part of entire inner surfaceof the nerve cuff.

In an embodiment, at least some electrical contacts 586 and pathways 584are positioned on the outside wall 582 b of the nerve cuff. In theexample of FIG. 42, therefore, the inner wall electrical contactstimulators will serve to stimulate at first nerve target such as thePTN, LPN, or MPN, and the outer wall stimulators can stimulate at secondnerve target such as the SAFN. Since the inner and outer walls 582 a,582b are non-conductive, when the contacts are positioned away from theedges then the stimulation of a target #1 should be well insulated andshould deter modulation of a second target #2. FIG. 42 is not drawn toscale and the arrow pointing to the left indicates that the nerve cuffcan be positioned close to, and even wrapped around, the PTN nerveduring implantation by a surgeon. In some anatomical regions the SAFN ismuch further from the PTN, and so a more appropriate embodiment would,for example, illustrate the nerve fiber on the left to be the LPN andthe nerve fiber on the right to be the MPN, which may have beendissected away from the remainder of the PTN nerve trunk. The cuff mayalso prove useful for selective LPN/MPN stimulation when implanted neara region where the PTN bifurcates into the LPN and MPN branches.

FIG. 42 also shows a microneurostimulator device 638 such as a batterypowered, wirelessly powered (e.g., RF/magnetic/microwave) driven devicewhich may be similar to that produced by, for example, Stimwave. Thedevice 628, may utilize RF energy for obtaining power wirelessly from anexternal device 636, as shown in FIG. 53a , configured for providingwireless power and data signals 646. Although the neurostimulators638,640 shown here do not have electrodes shown on their housing, it isunderstood that these, as well as those shown in other figures, may haveone or more electrode contacts disposed on their housing and that thesemay extend radially around their exterior or may be realized as aelectrode grid array on their surface that approximates theconfiguration found on a multi-polar paddle electrode and further thedevice 638 can communicate with electrode leads to provide stimulation.In an embodiment the device 638, or at least a portion of the device,can be injected into a nerve trunk such as the PTN during implantation,or injected into tissue proximate the PTN. The device 638 may haveelectrode contacts at its top and bottom surface which can providestimulation or the contacts may reside along the length of the device638, although these are not shown in every figure. When a single deviceis used, a pair of contacts may reside upon a particular portion thesurface of the device 638 in order to stimulate a nerve target disposedspatially (e.g., to the left) of the implanted device while the othercontacts reside on the opposite surface to stimulate a different nervetarget (e.g., to the right) relative to the position of the device.Similar to the IPC designs, device 638 may be provided with tines, oranchors, order to affix the device in position as well as having otherattachment means such as at least one ring along its body that allows asuture to be treaded through so that the device may then be sutured intoplace. In an embodiment where more than one device 638 is provided withthe first device may be implanted to stimulate a first target such asthe MPN and a second device 640 implanted to stimulate a second targetsuch as the LPN. When two or more neurostimulators 638, 640 areprovided, these can obtain power and be controlled from the sameexternal device EXD 636 which is configured to provide a combinationstimulation protocol by operating the two or more implanted devices inorder to realize a distributed neuro stimulation system 642.

U.S. Pat. No. 8,509,920 entitled “Electrode arrangements for medicallead”, incorporated herein by reference in its entirety for allpurposes, discloses an electrode lead which has multiple contactsarranged longitudinally along its inner surface. In embodiments relatedto the current invention, one or more electrodes may be employed toselectively apply an electrical signal to a particular set of nerves, ornerve fibers within a fascicle of the nerve.

An alternative nerve cuff design is shown on the right side of FIG. 42and includes a first cuff enclosure 592 and a second cuff enclosure 594which have independently operable electrical contacts 586 and pathways584 a,b (additional contacts and pathways are not shown for claritypurposes). A routing pathway 590 communicates signals between themulti-stranded stimulator electrode 588 (connected to theneurostimulator) and the conductive pathways 584 a,b so that stimulationsignals 588 reach their intended nerve target.

FIG. 43 shows an alternative embodiment of an implantable nerve cuff, inwhich electrode contacts 620 a,b may be located to stimulate a firstnerve target 1, and 620 c,d stimulate a second nerve target 2, usingstimulation signals supplied by the stimulator conduit 588 c. Theelectrode contacts may reside only on the inside or outside of the cuff,depending upon how the cuff is implanted by a surgeon. The nerve cuffitself may be made of conductive material (and may be coated partiallyor fully with non-conductive material).

In an alternative embodiment shown in FIG. 44, a nerve cuff electrodedesign is shown which may have two or three non-conductive, separationwalls 604 a, 604 b, 604 c which reside on non-conductive back-plate 602,which may be rigid, or made partially of a flexible material such assilicon. Each of two or more nerves are placed within the nerve cuff sothat each reside within one of the canals that are separated by thewalls 604. In an embodiment, a second (full or partial) back-plate isprovided opposite to the first back-plate 602 during implantation. Inthis manner, the walls can define enclosed pathways. The channels do nothave to be parallel and can be unequally spaced to conform to selectednerve targets.

In an alternative embodiment shown in FIG. 45, an implantableneurostimulator 600 can send signals to modulate two nerve targets, forexample, the LPN and MPN (in this case labeled Nerve 1 and Nerve 2) inan independent manner, by sending unique signals through multi-strandedpathways 588 a, 588 b to electrode contacts within the nerve cuffs 598a, 598 b. In an embodiment in which the nerve cuffs 598 a,598 b aresimply realized using conductive material, these may serve as thestimulators themselves and no contacts are provided. Nerve cuffs 598a,598 b may be serve as IPCs that are paired to work with an externalstimulator rather than working with an implantable device 600. In eithercase the partial or full cuffs can be formed or fabricated of a materialthat biases them in the closed position so that the inner space has aradius that can accommodate the nerve target. In an embodiment, thecuffs may also be made of a thin flexible conductive material thatallows the cuff to be gently wrapped around the nerve. The IPC can haveat least one surface that is electrically conductive so that an eTENScan be provided. In an embodiment an elastic or deformable cable can bewrapped around the cuff in order to bias it against the nerve and determigration. The IPCs may be realized using two different lengths and maybe implanted further away than shown, in order to increase the ease andaccuracy of providing selective nerve branch stimulation. Additionally,is understood that in figures shows a neurostimulator using a nervecuff, this could be realized using a lead-type single or multi-contactelectrode array such as is often used to provide stimulation of thebrain, spinal cord, or peripheral targets. For example, electrodes canbe realized as one or two column paddle type leads or passive tip leadswith steroid-elution coatings to improve post-surgical recovery. Inembodiments nerve cuffs can be configured with adaptors to attach toconduits provide by a neurostimulator in the case where an implantablepulse generator may subsequently use the cuff after eTENS to providestimulation.

In an alternative embodiment shown in FIG. 46, an implantableneurostimulator 600 can provide stimulation signals to modulate, forexample, the PTN and SAFN (in this case nerve 1 and nerve 2) to realizea selective nerve stimulation protocol. This can be achieved bypositioning the neurostimulator 600 at a location below the knee andnear a location where the SAFN stimulation has been found to beeffective. Electrode contact 589 a, can provide stimulation to the SAFN(Nerve 2) using a conductive region of the casing of the neurostimulator600, or a stimulation grid array which is designed to be the cathodeelectrode, and contact 598 a can serve as the anode or vice versa.Alternatively, contacts 589 a and 589 b may both be provided on thehousing, or using a grid array, to enable a more focal field of bipolarstimulation to be provided. Accordingly, in one embodiment theneurostimulator 600 can provide stimulation signals through themulti-stranded pathway 588, to electrode contacts within the nerve cuff598 a which may be located near the ankle and configured to stimulateNerve 1, while the neurostimulator is located higher in the leg and theneurostimulator housing, or contacts on the housing, provide stimulationof at least one branch of the SAFN.

In an alternative embodiment, the stimulator cuff 598 a may be realizedas a transverse intra fascicular multichannel electrode (TIME) which canbe inserted transversally for a peripheral nerve, such as the PTN, toselectively activate subsets of axons in different fascicles, such asthose of the MPN and LPN. Other embodiments may use longitudinal intrafascicular electrodes (LIFE), multichannel electrodes, or multipolarcuff electrodes can also be used (Badia et al. Comparative analysis oftransverse intrafascicular multichannel, longitudinal intrafascicularand multipolar cuff electrodes for the selective stimulation of nervefascicles. J Neural Eng. 2011 8(3):036023). In an embodiment the cuff iswrapped fully or partially around a vascular bundle and at last oneelectrode contact stimulator is configured to extend from a surface ofthe cuff and project into or near a nerve target in order to stimulatethat target. This may be surgically easier to achieve with less risk ofproducing nerve damage when providing, for example, selective nervestimulation of a nerve branch. Note that it may not be known which nervetarget of a nerve fascicle an electrode contact is stimulating duringthe provision of therapy. For example, if there are 4 contacts andcontact #3 successfully produces therapy, then it may not be knownwhether this occurs via the MPN, LPN, both, or otherwise. Thestimulation protocol or assessment procedure may simply be configured sothat a contact, or a combination of contacts, is used to providestimulation. The results disclosed herein serve to support the use of asystem which may use stimulation protocols and stimulators to stimulatedifferent nerve branches selectively. Accordingly, an embodiment issupported which uses a particular electrode contact of a set ofcontacts, or a particular set of contacts from a larger set (e.g. toprovide field steering). Prior to the results presented herein the PTNand its branches were treated as equivalent targets which would lead tosimilar results due to stimulation.

In an embodiment, a system for treating a patient with an overactivebladder condition is provided including a neurostimulator having aprocessor configured for operating a stimulation protocol to provide atleast one stimulation signal to at least one stimulator in order toprovide stimulation selectively to at least a first nerve target. The atleast one stimulator is adapted to be implanted within the patient andconfigured to selectively stimulate at least a first nerve target thatis a portion of the tibial nerve trunk at a location substantiallybetween a knee and a heel of the patient. The stimulator may have atleast a single electrode contact that is physically located next to aportion of the posterior tibial nerve that has been assessed as being asuitable target (during an assessment procedure). Alternatively,multiple contacts may be used. Use of combinations of stimulation signalcharacteristics (e.g., frequency, amplitude, polarity) and sets of 2 ormore electrodes which have been found to produce therapeutic results canbe set as values in a stimulation protocol which subsequently providestherapy to the patient. In this embodiment the stimulation systemoperates upon a strategy that recognizes that different branches of theposterior tibial nerve may produce different therapeutic effects,without requiring a particular electrode contact to be conceptually, orotherwise, mapped to a particular nerve target. Successful stimulationparameters can be assessed by trial and error, and then subsequentlyused. Nevertheless, when available, using anatomical landmarks, orimaging data, to align electrode contacts with particular nerve branchtargets may improve performance of the system and decrease the timeneeded to derive successful stimulation protocols.

In an alternative embodiment shown in FIG. 47, nerve cuffs 598 c, 598 dare shown in which the cuff itself is made of non-conductive material,or may have a metallic core and be insulated with a non-metallicmaterial. In this example, the electrode contacts 586 are configured tostimulate a nerve that is external to the nerve cuff. Alternatively oradditionally, contacts may be located on the inside wall of the nervecuff in order to stimulate the nerve within the cuff. The inner andouter electrode contacts 586 may be independently operable to provideseveral different stimulation signals. Although the nerve cuffs 598 c,598 d are shown as fully closed cylinders, this is to approximate theirclosed position and these can be uncoiled by opening up the cuff againstits biased, closed, position as is well known in the art. Target Nerves1 and 2 may be located near each other, or far away, such as the LPNbranches for the left and right side of the body and may be driven bytwo different neurostimulators.

In an alternative embodiment shown in FIG. 48, a nerve cuff 606 is shownand can be made of either a non-conductive and flexible substrate suchas silicone or a coated metal foil. The cuff 606 has at least-twoelectrode contacts 608 a, 608 b, and 608 c, which, in this example, areconfigured to stimulate three nerves or nerve fascicles. For example,contacts 608 a and 608 c are disposed on a first side of the cuff 606that faces into the page as indicated by their dashed-lines, while 608 bis on the second side, side facing out of the page. As in the otherdesigns, a multistranded cable 588 c can provide stimulation signals tothe stimulator contacts and additional contacts may also be provided toenable bipolar stimulation protocols. The right edge 609 of the cuff maybe extended in order to provide sufficient material to wrap the cuffaround all three nerves at least 1, 2 or 3 times in order to secure thecuff more firmly in place. The cuff can also be made of a biocompatiblematerial that is similar to cloth in texture and allows the nerves to begentle wrapped. Suture holes may also be provided into order to securethe wrapping and to secure the cuff to appropriate adjacent anchorpoints. In an embodiment, each of the electrode contacts can instead berealized by externally powered neurostimulators that reside in anon-conductive flexible material which may be wrapped around the nerve.

In an embodiment shown in FIG. 49, which is a top view, a nerve cuff 606is shown, with contacts 608 residing on the first (inner) surface of thecuff which has been concentrically wrapped around three nerves or nervebranches. Elements related to providing the electrical stimulation tothe contacts have been omitted from the figure for ease of viewing.Alternatively, a helical lead array, containing 3 loops which mayindividually engage the PTN, LPN, and MPN is an embodiment that may workwell to provide selective nerve stimulation.

The system may use one or more stimulator electrodes to stimulate anerve branch such as least one of the LPN and MPN and SAFN in severalmanners using the cuff designs disclosed in FIG. 42 to FIG. 47. In oneembodiment, at least one nerve branch, such as the LPN and MPN issurgically accessed by separating portions of the target nerve branchesfrom the full posterior tibial nerve trunk or by accessing the nervesadjacent to bifurcation. For example, a nerve cuff is attached to asection of the target nerve branch with electrode contacts configured toapproximately selectively stimulate the nerve branch, using a portion ofthe posterior tibial nerve trunk (e.g. near the ankle) that has beensurgically accessed. In this example, as depicted in FIG. 484, one nervecuff 598 a can be applied to, or near, a section of the LPN (Nerve 1, inthis example) and another 598 b can be used to stimulate a section ofthe MPN(Nerve 2, in this example). When the nerve cuff functions as apassive IPC that is not used with an implanted neurostimulator device600, then 598 a,b can simply be realized as conductive sleeves that arepaired to work with at least one external stimulator. When two sectionsof two nerve branches are targeted near the human ankle by dissectingthe PTN nerve trunk then during implantation the LPN and MPN can beidentified visually. Further, by stimulating the separated nerve sectionand ensuring that the associated sensed EMG activity (or visually seenmuscle movement) is recorded at the respective muscle group (e.g., bigtoe for MPN, or 3 smallest toes for LPN) can confirm the correctplacement of selection made visually. In this manner, the PTN, MPN, andLPN can all be stimulated from a single region.

In another embodiment, one or more nerve cuffs 598 (e.g., 598 c and 598d in FIG. 47) can also be used to facilitate selective activation ofnerve branches using percuteanous stimulation whereby the percutaneousneedle is positioned within the patient in order to make electricalcontact with at least one nerve cuff that has been implanted to enableselective modulation of the LPN, MPN, saphenous nerve, or other targetand facilitate the consistent provision of selective nerve branchstimulation. To clarify, percutaneous stimulation, without an IPC suchas a nerve cuff, may have difficulty in providing selective nerve branchstimulation to a patient when using a single entry point near the anklesince the nerves may be hard to find without surgery. One or more IPCsmay be configured on or near nerve targets and configured to receive theneedle. A patient or doctor can feel when the tip of the needle touchesthe implantable IPC. In another embodiment one or more stimulators aresimply positioned adjacent to each target nerve or nerve branch, withoutany dissection of the nerve trunk, in order to provide stimulation, suchas by and implanted device to an intended target.

The results of FIG. 41 indicate that size of current that is used tostimulate the saphenous nerve can be less (e.g. 16% to 50%) of theamplitude that is used to stimulate other nerve targets such as the LPNor MPN. In an embodiment, a range of approximately 0.025-0.10 mA may beused instead of approximately 0.12-0.18 mA range in a rat. If this lowerthreshold is also found in humans then this may offer the advantages ofdecreased amount of energy (e.g., voltage/current) and thus less drainon a battery that powers a neurostimulator, the ability to use a smallerbattery, providing a longer cycle between recharging, and less risk ofside effects such as pain, due to unintentional stimulation of lowernon-target lower limb muscles. Alternatively, higher amplitudestimulation may be used. When selective stimulation is directed at anerve branch, the aim is to stimulate that nerve branch and notunintended adjacent targets. In some embodiments disclosed in thisspecification, selective stimulation of the tibial nerve trunk indicatesthe intentional stimulation of the full trunk rather than the individualbranches.

As an alternative to adjusting the stimulation parameters (e.g.,amplitude, pulse width, and frequency), selective electrical activationof one or more subsets of SAFN fibers may provide an effective means ofachieving effect treatment of bladder dysfunction. As an example, FIG.50a shows a system for achieving this at the level of the lower leg,below the level of the knee. In humans, the SAFN exhibits multipledivisions that result in a plurality of distal branches innervatingdifferent cutaneous areas of the lower leg, ankle, and foot. At thelevel of the medial gastrocnemius muscle, a multi-contact electrode gridarray 610, having at least two contacts, on at least a top or bottomsurface of the electrode, can be implanted subcutaneously between themuscle and skin layers and can be powered by the stimulation module 54(depicted in FIGS. 18a and 18b ) of the implanted neurostimulator 632.This array 610 can be powered by various types of energy sources (e.g.,battery powered stimulation module or wireless powered stimulationmodule) that are connected via a multi-strand lead-wire 611 when thegrid is not formed onto the housing of a neurostimulator. Theneurostimulator 632 can be programmed to provide at least onestimulation signal to one or more rows or contacts on the grid array toprovide a spatially focused or distributed stimulation signal such thattherapeutic SAFN stimulation obtained. For example, the number andspacing of the active electrical contacts can be titrated to match thepreference or response profile of the patient. The patient may adjustthe contacts that are used in manual manner based upon a subjectiveexperience such as tingling, or this can be done using sensed data orotherwise. This type of approach may be particularly effective ifelectrical activation of one or more specific SAFN branch(es) causessevere painful sensations, that for example may be related to injury tothe corresponding or surrounding region of the lower leg (e.g.,allodynia).

FIG. 50a also shows another embodiment of a multipolar electrode of theinvention that can be implemented at or near the level of the medialmalleolus. This anatomical location provides access to both the SAFN andPTN. In this case, a linear (lead-type) electrode array 614 can beimplanted subcutaneously such that one or more of the electrode contactsare located in close proximity to one or more SAFN branch and also thePTN to provide stimulation of at least one of these targets. Thestimulator 632 (such as that shown in FIG. 53a ), which is connected viaa lead wire 611, can be programmed to deliver electrical pulses to oneor more of these neural targets such that effective treatment of bladdersymptoms is achieved. In two neurostimulators 638, 640 are also shownstimulating two branches associated with the SAFN that may be at thelevel of the knee or below.

Further alternative embodiments of systems and methods are shown in FIG.50b-e . FIG. 50b shows an implantable neurostimulator 670, with modulesincluding a control module 672 having a processor and circuitry forcontrolling the other modules, a power module 674 including batteryand/or antennae and/or induction coil as well as other circuitry forwireless power harvesting, regulation, and conversion, an AD/DA module676 which can include safety circuitry for ensuring that stimulation isprovided in a safe manner and configured for implementing stimulationand sensing operations under control of a therapy protocol as directedby the control module 672, and a communication module 678 configured toallow communication with other devices of a neurostimulation system suchas an external device (not shown). At least two stimulators 680 a, 680 bare provided on the housing 682 of the neurostimulator. The at least twostimulators can be realized in various manners, such as within astimulation grid array containing 2 rows each of 2 electrode contacts,or two ring electrodes that extend partially or fully around the housingof the neurostimulator 670.

In an embodiment of the invention, a neurostimulator may not be shapedor sized in order to provide stimulation to one or more nerve branchesthat may be distributed in space over a region that is larger than thestimulator. In order to address this problem, the neurostimulator can beoperated in collaboration with components that can extend thestimulation field across a larger area. FIG. 50c shows an electrode gridarray accessory 684 which can be realized to include at least: a supportstructure 686, which may be realized, for example, as a silicon diskwith or without internal or external skeleton components to assist withmaintaining shape; a receiving compartment 688 for receiving theneurostimulator 670, and electrode receiver contacts 690 which areconfigured to connect with stimulators provided on the neurostimulator.Additional elements may be included such as covers to provide a sealedconnection between the neurostimulator and the accessory and sutureholes to maintain the position of the accessory, etc. Further, as isshown in FIG. 50d , various elements of the accessory can assist instimulation being provided to adjacent tissue. FIG. 50d shows dashedlines representing various signal routing pathways 694 that connect eachof the electrode receiver contacts 690 to electrode contacts such as 692a, 692 b. The signal routing pathways 694 and associated stimulators 692a,692 b can operate in a fixed manner or a portion of the AD/DA module676 of the neurostimulation system can be disposed within the accessory684 and under control of the neurostimulator 670 or external patientdevice 72. One or more of the electrode contacts 692 a,692 b can belocated on a first surface (facing outward from the page) of theaccessory, on a second surface that is opposite to the first surface, orboth.

FIG. 50e , shows an embodiment an implanted neurostimulator 650 forstimulating both the SAFN and the PTN is shown having a first stimulator652 having at least one electrode configured to be implanted relativelyanterior (e.g., anterior to the medial malleolus) for stimulation of theSAFN and a second stimulator 654 having at least one electrode that isconfigured to be implanted relatively posterior (e.g., posterior to themedial malleolus) for stimulation of the PTN. A third electrode may bepositioned on a third stimulator 656 located part way between the firstand second stimulator in order to serve as an anode electrode while theelectrodes on the first and/or second, stimulator serve as cathode (orvice versa). Alternatively, rather than a single electrode contact thefirst and second stimulator 652,654 may each be configured with two ormore electrode contacts in order to provide two localized fields, forstimulating the PTN and SAFN in a bipolar fashion, respectively. In anembodiment, a pair of bipolar electrodes can be used to generatelocalized areas of neural activation (e.g., inter-electrode distance ofeach bi-pole between 3 and 5 mm and a stimulation amplitude up to 10 mA)and thereby independently stimulate each neural target. The threestimulators 652,654,656 are configured in an upside-down “Y”configuration, but other configurations are also possible to allow forstimulation of both the PTN and SAFN. For example, in an embodiment, aneurostimulator or stimulator connected 658 to a microneurostimulator660 can be realized as a multi-contact paddle electrode that isimplanted on the medial aspect of the lower leg (in ananterior-to-posterior orientation), such that it spans across a regioncephalad to the medial malleolus of a patient and a first set ofcontacts 659 are located anteriorly to stimulate the SAFN, and secondset of contacts are configured posteriorly to stimulate the PTN. Similarto neurostimulator 650, the neurostimulator 660 can be shaped to allowfor stimulation of both PTN and SAFN and the electrode contacts canreside on the housing.

Additionally, a neurostimulator with a grid electrode array 662 may bepositioned to stimulate both the SAFN at an anterior location and theSAFN at a posterior location, and the electrode contacts that areactivated during therapy can be selected or adjusted after implantation.Such a neurostimulator with a grid array 662 is shown in the figure forstimulating the LPN and/or MPN at a location below the medial malleolus.When a grid array stimulator similar to that of FIG. 50c-d is used, theposition of the electrode contacts can be formed into the supportstructure at locations selected due to imaging or other data related tothe patient.

Although the nerve stimulation systems can be provided to stimulate theSAFN and PTN branches at relatively anterior and posterior locations,respectively, nerve stimulation system configurations can utilizeelectrodes located only in locations posterior to the tibia/medialmalleolus. For example, a neurostimulator 660 with ring electrodescircumferentially disposed on its housing, can be positioned posteriorto the medial malleolus and configured to stimulate both the PTN andalso the SAFN fibers that either innervate the skin superficial to thePTN or continue subcutaneously to innervate skin areas caudad (ordistal) to the stimulating electrode location. In an embodiment, aneurostimulator 660 is positioned approximately 1.5 to 2.5 cm below theskin to target the electrical activation of the PTN, but the amplitudeis increased to a level sufficient enough to simultaneously stimulatethe SAFN branches or fibers that are located superficial to the PTN. Inan alternative embodiment, a neurostimulator is positioned 0.5 to 1.5 cmbelow the skin to stimulate the SAFN branches or fibers that terminatewithin or pass under the skin, but the amplitude is increased to a levelsufficient enough to simultaneously stimulate the underlying PTN. Inorder to allow the electric field to stimulate both neural targets, animplanted stimulator (for example, paddle type electrode) should haveelectrodes configured on both the side facing the skin to stimulate SAFNfibers and the opposite side facing the PTN. Additionally, aneurostimulator with circumferential ring electrodes can be used toachieve co-activation of SAFN and PTN fibers. In an embodiment designedto create a field capable of simultaneously stimulating both the PTN andthe SAFN branches/fibers, the inter-electrode spacing between activeelectrode contacts disposed on the surface of the neurostimulator 660,should be at least 5 mm, but preferably greater than 10 mm to create alarger stimulation field.

In an embodiment where a single set of electrodes, comprised of two ormore electrode contacts, are used to stimulate both the PTN and the SAFNbranches/fibers from the same stimulation signal field, a method mayinclude applying electrical pulses to one or more electrode contacts ofthe implanted device to activate both the tibial and SAFN cutaneousterminal fibers at least 50% of the time from the same field relative tothe activity which occurs in the absence of the stimulation.Alternatively, at least 2 different electrodes may be implanted andconfigured to simultaneously, or selectively, produce two fields thatare oriented for selectively modulating the PTN and cutaneous SAFNfibers, respectively.

It may be that using a single set of electrode contacts to stimulateboth the PTN and adjacent SAFN fibers can produce unwanted side effectssuch as subject discomfort. This is because the amplitude needed tostimulate both the PTN and the SAFN from the same electrodes will alsoincrease the risk of stimulation other sensory nerves that can cause thesubject discomfort or pain. In an embodiment, a neurostimulator is usedto provide a first field to stimulate the PTN using inward facingelectrodes disposed on an inward facing surface of the stimulator and asecond field to stimulate the PTN using outward facing electrodesdisposed on the outward facing surface of the stimulator. The stimulatormay be realized within a non-conductive substrate (e.g., silicone) suchas that shown in FIG. 50d with electrodes disposed on a first surfaceand second surface, to direct and bias the first and second fieldstowards their respective nerve targets.

It is likely that a neurostimulator such as a microneurostimulator (e.g.BION) intended to stimulate the PTN in isolation would be implantedclose to the PTN in order to maximize the intended therapeutic effectsof the stimulation while minimizing any potential side-effects caused bystimulation spillover. While this may improve stimulation of the PTN itmay decrease the ability of the neurostimulator to further augment thetherapeutic outcome by also activating SAFN branches/fibers located inproximity of the stimulating electrode. Accordingly, a method mayinclude positioning a neurostimulator at least 1 cm superficial from thePTN in order to improve the likelihood of stimulating both PTN and SAFNnerves. An alternative method for stimulating both the PTN and SAFN mayinclude positioning at least a first stimulator of an implantable deviceadjacent to or near the SAFN or PTN of a patient and then angling theneurostimulator to also provide stimulation of the other nerve targetrather than positioning and aligning the stimulator to only stimulateone of the two nerves. In an embodiment one end of a neurostimulator, oran electrode/contact of the stimulator is implanted at mostapproximately 1.5 cm from the PTN and the other end of theneurostimulator is positioned at most approximately 1.5 cm from theSAFN, or its cutaneous nerve terminals. For example, a neurostimulatorhaving electrodes on its surface, can be implanted so that one end ofthe stimulator is closer to the PTN than the SAFN and the other end iscloser to the SAFN than the PTN. The stimulation amplitude can then beset to cause stimulation of both the SAFN and PTN. An embodimentincludes positioning one or more electrodes of an implantable deviceadjacent to or near a SAFN or PTN branch of a patient and stimulatingwith an amplitude that causes activation of both nerves to increase byleast 50% over which occurs in the absence of stimulation.

An embodiment of a percutaneous treatment system is also shown that usespercutaneous needle electrode 657 to provide SAFN stimulation to apatient. After the needle 657 is inserted, for example, at a positioncephalad and anterior to the medial malleolus, a device 50 can be usedto provide a stimulation protocol similar to that used for PTNstimulation, with a current of about 0.5-9 mA (increased until a patientfeels a cutaneous sensation) presented at 10 or 20 Hz to providestimulation during a treatment session lasting about 30 minutes. Aconductive pad with at least one conductive portion can serve as areturn electrode and or ground is placed over the medial aspect of thecalcaneus and also connected to the device 50. Treatment may have bothan induction interval, with weekly or bi-weekly stimulation sessions,followed by a maintenance interval of less frequent treatment. Thestimulator may allow the user to also select or configure additionalprotocols. For example, a user can independently modify the frequency,amplitude, and time using a graphical control and “+”, “−” buttons tochange the values. Additionally, the user can choose from, or create,additional protocols. A protocol parameter can be called “ramp mode”,which when selected causes a selected stimulation parameter such asstimulation amplitude to vary over a range such as +/−2 uA during thesession instead of maintaining a constant value. One protocol can becalled “10/20”, which stimulates for 50% of the time at 10 Hz and theother 50% at 20 Hz.

In an embodiment shown in FIG. 54, an implanted neurostimulator device632 b can provide stimulation signals to an IPC nerve cuff or lead-typemulti-contact electrode array 598 f, configured to stimulate a target inthe medial aspect of the ankle region such as the PTN or SAFN using astimulator conduit 84 b. The nerve cuff 598 f may be configured with twoor more independently operable electrodes to provide localized bipolarstimulation of a target nerve, or may only include a single electrodeand the return path is provided by a stimulator on the neurostimulatordevice 632 b. In the latter case, the cuff 598 f can be implanted andconfigured to activate electrically the PTN or SAFN near the medialmalleolus, while the stimulator provided on the neurostimulator device632 b can serve to stimulate the SAFN in the leg, such as the SAFN nerveor it branches which terminate in the skin. In one embodiment, theneurostimulator is implanted and operated to cause the nerve cuff tostimulate the PTN using a monopolar electrode and the return path isbetween the neurostimulator and the nerve cuff. The stimulationamplitude is then increased until the subject senses a tingling in theirleg and then more, less, or an equal amount of stimulation is providedduring subsequent therapy. Additionally, at least one electrode used toprovide stimulation near the neurostimulator device can be made largerto increase the chance of stimulating cutaneous branches of the SAFN.

Additional System Embodiments

In an embodiment, electrical activation of SAFN afferents is achieved bydelivering stimulation at the level of the spinal cord. As shown in FIG.51, a multi-contact grid electrode array 612 having at least 2 contactscan be implanted near the dorsal surface of the lumbar spinal cord suchthat one or more electrode contacts are able to selectively activatenervous tissue with electrical pulses. A single electrode array 612 maybe constructed large enough to provide electrical pulses at targetsalong the entire L2-L4 region or it may be small enough to be implantedthrough, or adjacent to, respective foramen and to stimulate a specificregion (e.g., L4). A single array or multiple arrays may be used tocapture complementary subsets of nerve roots located at targetanatomical locations (e.g., L2 and L4 stimulation). The array 612 may beimplanted external to or underneath the dura to provide more selectiveelectrical nerve stimulation.

An embodiment includes a method of electrically activating spinal nerveroots within the region of the lumbar spinal cord using a lead-typemulti-contact electrode array 614. Mechanical stability may be improvedusing a tined array design. In FIG. 51 the lead-type array 614 ispositioned (e.g. rostro-caudally) such that one or more spinal nerveroots (e.g. L3 and L4) is selectively activated. The clinician mayprogram a neurostimulator to stimulate two or more nerve rootssynchronously, alternatingly, out-of-phase, or can select stimulation ofonly one nerve root. Alternatively, the lead-type array 614 ispositioned (e.g., anterior-posterior direction) such that only onespinal nerve root (e.g., L4) is targeted, but the multiple stimulationsites provide for selecting one or more channels (e.g., monopolar,bipolar, or tripolar) for treatment of bladder symptoms. In anembodiment, the lead array 614 or stimulators 638 may stimulate a spinaltarget by implantation adjacent to the associated foramen and may residein the epidural space. The lead can be spiral and reside around a nerveroot, upon lumbar vertebra or about the sacrum.

FIG. 52 shows method for providing nerve stimulation including the stepsof assessing implantation sites and parameters 622, implanting aneurostimulation system components 624, including at least onestimulator, and providing therapy 626. In an embodiment, steps includingassessing sites and parameters 628, and adjusting at least one of thesites and parameters 630 may be done in order to provide stimulationthat has therapeutic benefit. A stimulation assessment protocolcomprises a patient being stimulated before, during or after one or more“assessment interval”. Stimulation signals which meet treatment acriterion provide improved therapy are selected and stored to define thesignals and sites of therapy protocols subsequently used duringtreatment.

In an embodiment, a method of treating OAB includes combination therapy.The provision and operation of a neurostimulator having a processorconfigured for operating a stimulation protocol that provides at leastone stimulation signal to at least one stimulator for providingselective stimulation of at least one nerve target; and, the at leastone stimulator is configured to selectively stimulate at least a firstnerve branch nerve target of the SAFN or one PTN branch at a locationapproximately between the knee and the heel; and, the at least onestimulator provides at least one electrical stimulation parameterassessed to be effective to at least a first nerve branch. The provisionof a drug therapy 629 can also occur. A target such as the PTN, MPN,LPN, SAFN at peripheral site or associated spinal root. The drug therapy629 can involve oral ingestion of a drug such as an anti-cholinergics,or transurethral or intrathecal injection of a drug such as botox intothe bladder wall (e.g., as may occur intravesicle). The drug therapy mayenable the nerve stimulation to be more effective in bladder inhibitionand patient tolerance to stimulation. The drug therapy may involvetitrating the dosage of a drug such as botox (e.g. volume per injection,drug concentration, number of locations within the bladder) to enable abroader range of peripheral nerve stimulation parameters to be used toprovide effective bladder inhibition. The electrical stimulation mayenable less dosage or frequency of drug therapy needed to sustaintreatment of OAB. The electrical simulation may enable the drug therapyto occur with smaller volume or lower concentration of intra-vesicallyinjected botox, such as to minimize the incidence of urinary retention(i.e., need for urethral catheterization).

FIG. 53a shows a neurostimulator system 644, having a neurostimulator632, and sensor 634, and which is configured to communicate with anexternal programmer EXD 636 using wireless signals 646. In oneembodiment the EXD 636, can provide both communication and powerwireless signals 646 in order to provide power. The neurostimulator 632can be configured with multiple conduits to provide stimulation to atleast one target nerve (T1-T4). An EXD patient programmer 636 orneurostimulator 632 can operate a processor to provide therapy programthat using, in part, a historical patient record algorithm defined inthe protocols and parameters module 66. The algorithm can operate toobtain, assess, and store a historical patient record in, for example,memory 60. The historical record stored in memory 60 can include, forexample, 1) all parameters, adjustments, and times related tostimulation, 2) a record of the system alerting a patient by, forexample, sending a communication signal to the EXD 636, or triggered bytime intervals expiring, time of day, or sensed data meeting one or moretreatment criteria, 3) patient input data, including input by thepatient into the EXD 636 that caused stimulation to be delayed 4)patient diary information such as subjective information input by apatient using the EXD 636 as may occur spontaneously, according to aschedule, and/or in response to questions posed to the patient by theEXD (or realized by a smartphone application operating on the patient'scellphone), about voiding, subjective scores related to voiding urgency,pain, sensitivity, etc.

In an embodiment, a system for treating incontinence can comprise: asensor 634 which is part of a sensing module 55 which is adapted togenerate a signal responsive to a state of a patient related to bladderor bowel activity; at least one stimulator 114 having an electrode, thestimulator adapted to modulate a pelvic floor activity of the patient bystimulation of at least one spinal target such as L2, L3 L4; and acontrol module 52 of a neurostimulator device 632, which is adapted toreceive the signal from the sensing module, to analyze the signal so asto detect an event related to bladder or bowel activity, and, responsiveto detection of the event, operate to make an adjustment in thestimulation protocol of the protocols and parameters module 66 to causea change in the nerve modulation provided to the at least one electrode.The adjustment to the stimulation protocol can be starting or increasingthe strength of modulation when an event is detected. The control module52 can be adapted to apply a first waveform to the stimulator responsiveto determining that the detected event is related to an incontinenceevent that is imminent, and wherein the control module is adapted toapply a second waveform, different from the first waveform, responsiveto determining that the event is not imminent. The detected event may berelated to an incontinence event that is eminent and is detected whensensed activity is above a threshold set for the patient. In anembodiment, the first waveform is related to deterring the acuteresponse of the bladder to stimulation and the second waveform isrelated to the deterring the prolonged response of the bladder tostimulation. The sensor can be implanted and configured for measuringmuscle activity related to fecal or urinary voiding. Instead of, or inaddition to, bladder modulation, the stimulation may also be orientedtowards modulation of other tissue, for example, it may promote analsphincter muscle contraction.

When a sensor is not used, a method of treating a patient may simplycomprise: with a processor of the control module 52, controlling astimulation generator of a neurostimulator 632 to deliver electricalstimulation to one or more tissue sites proximate to one or more spinalnerves from L2 to S4 of a patient, in a frequency dependent manner, togenerate an inhibition or excitation bladder activity related tovoiding, as per a therapy protocol. The stimulation protocol implementedby the system 644 is configured so electrical stimulation delivered atone of the one or more tissue site to be a stimulation signal having afrequency that has been shown in a patient to lead to decreased bladdercontraction as part of a bladder relaxation therapy protocol provided bythe processor in order to decrease voiding activity. The stimulationprotocol defined in protocol module 66 is configured so electricalstimulation delivered at one of the one or more tissue site comprises astimulation signal having a frequency that has been shown in a patientto lead to increased bladder contraction as part of a bladder excitationtherapy protocol in order to increase voiding activity.

FIG. 53b shows a system having a neurostimulator device 638 such as awirelessly powered device which may harvest wireless power to stimulateat least a first nerve target. An external device 636 is configured forproviding wireless power and data signals 646 to the device 638 torealize a stimulation protocol. A second neurostimulator device 640 mayalso be provided to stimulate a second target. When two or moremicroneurostimulator devices 638, 640 are provided, these can obtainpower and be independently controlled from the same external device EXD636. The EXD 636 has a processor which is configured to operate the EXDto provide a stimulation protocol by operating the two or more implanteddevices that work as a distributed neurostimulation system 642. Whenmultiple devices 638, 640 provide at least one stimulation protocol thenthese can cooperate, for example, to provide stimulation of multipleSAFN branches.

FIG. 54 shows a first neurostimulator system 644 in the leg of a patient8, with a neurostimulator device 632 a which provides stimulationsignals to a IPC nerve cuff 598 e using a stimulator conduit 84 a. Asecond neurostimulator system 644 is also shown in the lower leg of apatient 8, with a neurostimulator device 632 b which providesstimulation signals to an IPC nerve cuff 598 f configured to stimulate atarget in the medial malleolus such as the PTN or SAFN using astimulator conduit 84 b. US Pat App #20080234782, to Haugland,incorporated by reference herein discloses various systems and methodsthat can be used when implementing stimulation protocols and systems ofthe present invention in the leg of a patient.

In an embodiment, a system to modulate bladder activity for treating apatient having a bladder dysfunction or disorder includes a processorfor operating a signal generator of a stimulation module according to astimulation protocol to provide a first stimulation signal andneurostimulator configured to provide the stimulation signal to astimulator adapted to be positioned below the knee of the patient andadjacent to a portion of a SAFN of the patient for stimulating the SAFN,whereby bladder activity is modulated. The stimulation protocol definesa stimulation signal to have a frequency selected to provide aninhibitory effect of bladder activity such as within the approximaterange of 10 Hz to 20 Hz a frequency selected to be substantially in atleast one of a 2 Hz range and 50 Hz range to provide an excitatoryeffect on bladder activity. The stimulation signal can be selected tohave a predetermined combination of frequency and amplitude determinedto increase or decrease bladder activity of the patient during aprevious assessment interval or has been shown in a previous sample ofpatients to increase or decrease bladder activity. The stimulator isadapted to be positioned adjacent to a portion of the SAFN of thepatient for providing stimulation at a location that is cephalad to themedial malleolus and anterior to the medial malleolus within theapproximate range of 1 to 3 cm or cephalad to the medial malleolus andposterior to the saphenous vein at a displaced distance within theapproximate range of 1-2 cm, and at a subcutaneous depth within theapproximate range of 0.5 cm and 1.5 cm or at a location adjacent to theanterior side or posterior side of the medial malleolus, adjacent to theposterior side of the medial malleolus. Alternatively, a stimulator ispositioned on a housing of the neurostimulator implanted at a positionproximate to a medial malleolus of the patient and adjacent to a portionof the SAFN of the patient. The position is also adjacent to a portionof the PTN with the neurostimulator being configured to providestimulation using at least two electrode contacts on the stimulatorconfigured with an inter-contact distance of at least 5 mm. Further, thestimulation signal can have an amplitude sufficient to provideconcurrent stimulation of the PTN and at least one branch of the SAFNthat is located superficial to the PTN. Additionally, in an embodiment,the system having a processor for operating a signal generator of astimulation module according to a stimulation protocol can be configuredto provide at least a second stimulation signal from a second stimulatoradapted to be positioned below a knee of the patient and adjacent to aportion of a posterior tibial nerve of the patient and configured toprovide stimulation of the posterior tibial nerve in order to modulatebladder activity. The stimulation module can use a stimulation protocolconfigured to provide the first stimulation signal and secondstimulation signal substantially simultaneously or at differing times todeter interaction effects between the first and second stimulationsignals. The first stimulation signal and second stimulation signal canoccur at the same or different frequencies, and may be unique instimulation parameters. In an embodiment, the first stimulator is anelectrode implanted at a location that is approximately 3 cm to 5 cmcephalad and 1 cm to 2 cm anterior to a medial malleolus of the patientand the second electrode is implanted at a location that isapproximately 3 cm to 5 cm cephalad and approximately 1 cm to 3 cmposterior to the medial malleolus. The system may have one stimulatorthat is adapted to be positioned adjacent to a portion of the saphenousnerve of the patient for providing cutaneous stimulation at a locationthat is on the medial side of a leg of the patient and within theapproximate range of 3 cm to 10 cm below a knee of the patient. Further,the stimulator may be adapted to be positioned adjacent to a portion ofthe saphenous nerve of the patient for providing cutaneous stimulationat a location that is on the medial side of the leg within theapproximate range of 3-10 cm below a knee of the patient and thestimulation signal is provided to at least one branch of the saphenousnerve at approximately an amplitude that produces a cutaneous sensationin the lower part of a leg of the patient.

In an embodiment, a stimulation target nerve can be selected at alocation below a pelvis region of the patient, such as near the femoralnerve of the patient substantially above the knee for targeting andstimulating the SAFN of the patient. Providing stimulation of thesaphenous nerve can entail providing a low amplitude stimulus within therange of 25 uA-75 uA for stimulating the SAFN since it has been shown tomodulate bladder activity with as little as 25 uA. Alternatively, thesystem can provide stimulation substantially at the level of the spinalcord to stimulate at least spinal roots that are associated with theSAFN. Stimulation therapy can be provided according to a first protocolto cause an acute change to bladder activity approximately during thestimulation interval or second protocol designed to cause a prolongedchange to bladder activity lasting after the end of a stimulationinterval, or both, where the acute stimulation occurs as needed. Forexample, the system, when implanted, can include a sensor and a sensingmodule as well as a control module configured to process sensed data,detect events in the sensed data, and adjust stimulation provided by thestimulation module to provide stimulation related to acute bladdermodulation based upon the detection of at least one event in the senseddata related to for example, bladder activity and bladder volume.Alternatively, the stimulation protocol can simply adjust a stimulationcharacteristic if a first stimulation protocol does not providesufficient modulation of bladder activity. Adjusting stimulation caninclude adjusting a frequency of modulation or implementing astimulation signal that varies over time, such as a chirp. Themodulation of bladder activity is provided in order to provide therapyto the patient in response to an unwanted symptom and the results ofproviding therapy can be to relieve symptoms which in embodiments can beconsidered as resulting from modulation of bladder activity.

In an embodiment, a method for treating overactive bladder includesestablishing a neurostimulator having a processor configured to providea stimulation protocol that provides stimulation at a stimulator tomodulate the SAFN and also at a second stimulator to stimulate the PTN,or the LPN/MPN branches at a location substantially between a knee and aheel of the patient. The method further includes applying an stimulationsignal using parameters found to be effective to at least a one of thenerve targets and also providing a drug therapy to the patient.

In an embodiment, a system for treating a patient with an OAB conditionincludes a neurostimulator having a processor configured to provide astimulation protocol that independently provides a stimulation signal toa stimulator for providing selective stimulation to a first nerve targetand the stimulator is adapted to be implanted within the patient andconfigured to selectively stimulate a first nerve target that is a PTN,LPN, or MPN at a location substantially between a knee and a heel of thepatient. the system is further configured with a stimulator implanted tostimulate an additional target of the SAFN, to provide a combination ofconcomitant electrical activation of the SAFN and at least one of thePTN, LPN, and MPN. The stimulator can have a first electrode contact anda second electrode contact which are supplied using a nerve cuff havinga non-conductive inner annular wall, and a first electrode contactconfigured to stimulate the first target nerve branch and an outerannular wall that is non-conductive and a first electrode contact thatis positioned to stimulate a second target.

In an embodiment, a system is configured to provide therapy to a patientsuffering from an overactive bladder disorder comprising a firststimulator implanted in the patient and configured to selectivelyprovide stimulation to at least a first nerve target and a second nervetarget. The first nerve target is selected from the group of nervetargets: PTN, LPN, MPN, and SAFN, and the second nerve target selectedto be a different target within the group of targets than that selectedfor the first nerve target. Additionally, at least one neurostimulatoris configured for providing a stimulation protocol which is configuredwith at least a first stimulation signal to be applied to the firstnerve target and a second signal to be applied to the second nervetarget, wherein the stimulation protocol defines a first parameter valuefor the first signal and a second parameter value for the second signaland the first and second parameter values are selected to include atleast one parameter value from the group of (1) stimulation frequencyfor determining the frequency of the two stimulation signals and (2)stimulation amplitude for determining at least one of the current orvoltage of the two stimulation signals. The first and second stimulationsignals are selected to be signals that have been assessed to providedesired modulation of bladder activity in the patient or in a samplepopulation. In an embodiment, the second stimulation signal is appliedby the stimulation protocol to the SAFN and the current or voltage ofthe stimulation signal is approximately 30%-60% less than the value usedfor the first stimulation signal. the first signal and secondstimulation signals can be to be signals that have been assessed ashaving therapeutic efficacy in the patient when presented in combinationto each of two target nerves.

In an embodiment, a system is configured to treat pelvic floordysfunction or provide relief of symptoms in a patient comprising aneurostimulator having a stimulator configured to stimulate a firstnerve target with a first stimulation signal and a second nerve targetwith a second stimulation signal, wherein the first stimulation signalis selected to be therapeutic at the first stimulation target and thesecond stimulation signal is selected to be therapeutic at the secondstimulation target, and the first and second stimulation targets areselected to be at least two of the set including: PTN, LPN, MPN, andSAFN.

In an embodiment, a system is configured to treat a bladder disorder andcomprises an implanted neurostimulator having a stimulation protocolwhich is configured to apply a first signal a first nerve target, thesignal having been previously assessed as producing inhibition ofbladder activity and additionally apply a second signal to a secondtarget to produce excitation of bladder activity. The first stimulatorcan be implanted in a patient and configured to selectively stimulate atleast a first nerve target selected from the group of: PTN, LPN, MPN,and SAFN. The first and second nerve targets can be the same nervedifferent targets. Additionally, the second stimulation signal isselected to be approximately above 35 Hz and below 100 Hz, for causingexcitation of bladder activity.

In an embodiment, a system is configured to modulate voiding activityand/or related symptoms of a patient. The system can include aneurostimulator having a control module processor configured to controla stimulation module with a signal generator to provide a first therapyprotocol that is configured to provide stimulation to a firststimulation site using a first stimulation signal having a firststimulation pattern that is selected to increase voiding activity and asecond therapy protocol that is configured to provide stimulation to astimulation site using a second stimulation signal having a secondstimulation pattern that is selected to decrease voiding activity; and,a stimulator is configured to receive a stimulation signal from theneurostimulator and to stimulate a nerve target for at least onestimulation site. The at least one stimulation site for the firststimulation signal is a site selected for stimulating a nerve targetselected from the set of nerves including. PTN, LPN, MPN, and SAFN.

In an embodiment, a system for treating overactive bladder comprises aneurostimulator, an external device which is a patient programmer, aprocessor for implementing a stimulation protocol which definesstimulation provided to a patient which is configured to stimulate afirst candidate nerve target site with at least a first candidatestimulation signal applied to at least a first stimulator that receivesthe signal from the neurostimulator, adjust the protocol to adjust theat least one of the first candidate nerve target site or the firstcandidate stimulation signal, wherein the adjustment to the candidatenerve target site includes switching between at least two candidatenerve target sites selected from the group of: PTN, LPN, MPN and SAFN.Additionally the stimulation protocol is configured to stimulate atleast two of the sites using at least the first stimulator. Thestimulation protocol adjustment can contingently occurs during theprovision of therapy. It can occur after stimulating the first candidatenerve target site with the first candidate stimulation signal and thendetermining if there is therapeutic benefit that meets a treatmentcriterion; and, if the criterion is met continuing to stimulate usingthe first candidate nerve target site and first candidate stimulationsignal; and if the criterion is not met performing the step of adjustingthe protocol and providing stimulation. Additionally, the adjustment ofthe protocol can contingently occur prior to, or intermittently during,the provision of therapy and includes: stimulating the first candidatenerve target site with the first candidate stimulation signal;collecting and storing or treatment data related to the efficacy of thestimulation in treating the disorder; adjusting the protocol to realizea treatment site and stimulation signal combination according to aprotocol that is defined to realize a series of stimulation sites andstimulation signals; and, evaluating the treatment data to select atleast one stimulation site and stimulation signal combination whichprovided improved therapy to the patient. The adjustment of the firstcandidate stimulation signal can include adjusting the frequency of thestimulation signal. Adjustment of the first candidate stimulation signalcan also include switching between at least two of the frequenciesselected from the group: 2 Hz, 5 Hz, 10 Hz, 15 Hz, 20 Hz, and 50 Hz, andfurther, if the two or more frequencies do not produce a therapeuticeffect then assessing frequencies either above or below this range.

In an embodiment, a system is configured to treat a patient sufferingfrom OAB comprising a stimulator implanted in a patient and configuredto stimulate a first spinal nerve root target selected from the nervegroup of: L2, L3 and L4. The stimulation can occur at between 5 and 50Hz, and may preferably occur at 10 to 20 Hz when bladder inhibition isdesired. The implanted neurostimulator has a stimulation protocolconfigured to apply a first stimulation signal to the first spinal nerveroot target to modulate bladder activity and or relieve symptoms. The atleast first spinal nerve root target can be selected to provide for bothinhibition and excitation of bladder activity by using two differentstimulation protocols. Alternatively, the spinal nerve root targetsincludes at least two spinal nerve root targets that are each selectedto provide at least one of inhibition and excitation of bladderactivity. Two different stimulation protocols can define stimulationsignals with different frequencies and/or amplitudes for the one or two.The first stimulation signal can be selected to have a frequency whichproduces at least bladder activity inhibition or excitation in thepatient. The system can include a second stimulator selected tostimulate a second nerve root target from a nerve group. The secondstimulator can be selected to stimulate a second nerve root target froma nerve group of targets being L3 and L4. The second stimulator can beimplanted in a patient and configured to stimulate a second spinal nervetarget selected from the group of: L5, S1, S2, S3, and S4, which ispreferably S3.

In an embodiment, a system is configured to treat a patient sufferingfrom OAB and includes a first stimulator implanted in a patient andconfigured to stimulate at least a first spinal nerve root targetselected from the group of: L2, L3, L4, and a second stimulatorimplanted in a patient and configured to stimulate at least a secondspinal nerve root target selected from the group of: L5, S1, S2, S3, andS4. The implanted neurostimulator has a control module with a processorconfigured to implement a stimulation protocol which is configured toapply at least a first modulation signal to the first stimulator tomodulate the first spinal nerve root target and a second modulationsignal to the second stimulator to modulate the second spinal nerve roottarget. The modulation signals for modulating the first and secondspinal nerve root targets can be independently set, and/or adjusted, bythe stimulation protocol. The first modulation signal is selected to bea signal that has been assessed to produce therapeutic efficacy in thepatient or which has been assessed to produce therapeutic efficacy in asample population. Additionally, the first modulation signal and secondmodulation signal can be selected to be signals that have been assessedto produce therapeutic efficacy in the patient when presented incombination. Further, the first modulation signal and second modulationsignal can be selected to be signals that have been assessed to producetherapeutic efficacy in the patient when presented together compared tothe efficacy of the first modulation signal and the second modulationsignal when presented alone. Additionally, the first modulation signalprovided at the a first stimulator can be configured to stimulate atleast a first spinal nerve root target selected from the group of: L2,L3, L4. The stimulation amplitude can be made sufficient to produceactivation of somatic fibers used to achieve modulation effects.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein.

The various steps disclosed herein (such as, for non-limiting example,logic that performs a function or process) may be described as dataand/or instructions embodied in various computer-readable media, interms of their behavioral, and/or other characteristics. The logic andmethods described herein may comprise, according to various embodimentsof the invention, software, hardware, or a combination of software andhardware.

Unless the context clearly requires otherwise, throughout thedescription and the claims, the words “comprise,” “comprising,” and thelike are to be construed in an inclusive sense as opposed to anexclusive or exhaustive sense; that is to say, in a sense of “including,but not limited to.” Words using the singular or plural number alsoinclude the plural or singular number respectively. When the word “or”is used in reference to a list of two or more items, that word coversall of the following interpretations of the word: any of the items inthe list, all of the items in the list and any combination of the itemsin the list.

What is claimed is:
 1. A method for treating a patient having a pelvicfloor dysfunction or overactive bladder disorder including: establishingat least a first neurostimulator having a processor and an electricalsignal generator for generating at least a first stimulation signal inaccordance with a stimulation protocol; configuring said processor toset at least one of a plurality of stimulation parameters of astimulation protocol, with parameter values effective in treating atleast one symptom of a patient's pelvic floor dysfunction or overactivebladder disorder when said at least first stimulation signal is appliedto a saphenous nerve of a patient; configuring said at least firstneurostimulator to provide said at least first stimulation signal to atleast a first stimulator in accordance with said stimulation protocol;positioning said at least first stimulator adjacent to a portion of asaphenous nerve of the patient for stimulating the saphenous nerve;operationally activating said processor coupled to said electricalsignal generator according to said stimulation protocol to provide saidat least first stimulation signal; and, applying said at least firststimulation signal to said at least first stimulator, whereby saidpelvic floor dysfunction or overactive bladder disorder is treated. 2.The method of claim 1 wherein said plurality of stimulation parametersis selected from the group of: frequency values, amplitude values,frequency value ranges, amplitude value ranges, duration of stimulationvalues, duty cycle values, bursting pattern, burst or non-burst pulsetrain characteristic values, shape of the stimulation pulse or waveformvalues, pulse width values, pulse shape values, or polarity, andcombinations thereof.
 3. The method of claim 1, wherein the stimulationprotocol defines said at least one stimulation signal to have afrequency selected to be effective in providing an inhibitory effect ofbladder activity, wherein the frequency is selected to be within theapproximate range of 10 Hz to 20 Hz.
 4. The method of claim 1 whereinthe portion of a saphenous nerve of the patient is a portion of a lowerlimb of the patient.
 5. The method of claim 1 wherein the at least firststimulator is selected from the group of: an electrical stimulator, amagnetic stimulator, a vibrating stimulator, an ultrasonic stimulator, apercutaneous needle electrode, a transcutaneous electrical nervestimulation electrode, a magnetic stimulator, a nerve cuff, a conductiverod, a paddle electrode, an implanted electrode, a multipolar lead-typeelectrode, an electrode on the housing of an implanted neurostimulator,an implanted grid electrode array, and a transcutaneous electrical nervestimulation electrode configured to operate with an implanted passivecomponent having a conductive portion.
 6. The method of claim 1 whereinthe stimulation protocol defines the at least one stimulation signal tohave a frequency value parameter value selected to be effective inmodulating bladder activity wherein the frequency parameter value isselected to be within the approximate range of 2 Hz to 50 Hz when thestimulation protocol is defined to provide stimulation to providesymptom relief either at the time of stimulation or afterwards.
 7. Themethod of claim 1 wherein the stimulation protocol defines said at leastone stimulation signal as having a predetermined frequency that has atleast one of the group of: being determined to improve at least onesymptom of the patient during a previous assessment interval and, beingdetermined to improve at least one symptom of a group of patients duringa previous assessment interval.
 8. The method of claim 1 wherein said atleast one stimulator is adapted to be positioned adjacent to a portionof the saphenous nerve of the patient for providing stimulation at alocation that is on the medial side of the leg and the at least onestimulation signal is provided at approximately an amplitude thatproduces a cutaneous sensation or paresthesia.
 9. The method of claim 1,wherein the at least first stimulator for stimulating the saphenousnerve is an external transcutaneous electrical nerve stimulationelectrode and the system also includes a second stimulator forstimulating the posterior tibial nerve, and the second stimulator is animplanted electrode that operates with an implantable neurostimulator.10. The method of claim 1, further configured to provide at least asecond stimulation signal from a second stimulator adapted to bepositioned adjacent to a portion of a nerve in the lower limb of thepatient.
 11. The method of claim 1, further configured to provide atleast a second stimulation signal from a second stimulator adapted to bepositioned adjacent to a portion of a nerve in the lower limb of thepatient, and that nerve is not the saphenous nerve and stimulation isprovided using a combination of at least two nerves.
 12. The method ofclaim 1, wherein said pelvic floor dysfunction or overactive bladderdisorder is selected from the group of at least one of overactivebladder, urinary frequency, urinary urgency, urinary incontinence, fecalincontinence, stress incontinence, urinary pain, pelvic pain, urinaryretention, or sexual dysfunction, and combinations thereof.
 13. Themethod of claim 1 wherein said at least first stimulator is adapted tobe positioned adjacent to a portion of the saphenous nerve of thepatient for providing a stimulation at a location that is cephalad tothe medial malleolus and posterior to the saphenous vein at a displaceddistance within the approximate range of 1-2 cm, and at a subcutaneousdepth within the approximate range of 0.5 cm and 1.5 cm.
 14. The methodof claim 1 wherein positioning said at least first stimulator adjacentto a portion of a saphenous nerve of the patient for stimulating thesaphenous nerve includes providing the at least one stimulator on awearable garment.
 15. The method of claim 1 further including providingand operating at least one sensor to obtain sensed data that is one of:electrical, related to nerve activation, an electromyogram related toevoked muscle activity, accelerometer data, and optical data.
 16. Themethod of claim 1 further including: providing and operating a controlmodule configured to obtain user input and provide communication withand control of the processor; providing and operating at least onesensor for obtaining sensed data or communication module for allowingpatient data input, said sensed data or patient data serving as feedbackdata; wherein the control module controls the processor to operate uponthe feedback data, to evaluate the feedback data and to cause the systemto: adjust one or more parameters of the first stimulus based at leastin part on the evaluation of feedback data; and provide the firststimulus signal to the saphenous nerve to treat a patient's pelvic floordysfunction or overactive bladder symptoms.
 17. The method of claim 1further including: providing and operating a control module configuredto obtain user input and provide communication with and control of theprocessor; providing and operating a communication module for allowingpatient data input, said patient data serving as feedback data; whereinthe control module controls the processor to operate upon the feedbackdata, to evaluate the feedback data and to cause the system to: adjustone or more parameters of the first stimulus based at least in part onthe evaluation of feedback data; and provide the first stimulus signalto the saphenous nerve to treat a patient's pelvic floor dysfunction oroveractive bladder symptoms.
 18. The method of claim 1, whereinpositioning said at least first stimulator adjacent to a portion of asaphenous nerve of the patient for stimulating the saphenous nerveincludes positioning the stimulator on the patient's skin to stimulatethe saphenous nerve of the patient, the method further comprising thesteps of: positioning a second stimulator on the patient's skin tostimulate the posterior tibial nerve of the patient; delivering a firstelectrical nerve stimulation signal transcutaneously to a first nervewhich is the saphenous nerve through the at least first stimulator; and,delivering a second electrical nerve stimulation signal transcutaneouslyto a second nerve which is a nerve of the lower limb through the atleast second stimulator; whereby combination stimulation of thesaphenous nerve and at least one other nerve of a lower limb aremodulated at times selected from the group of: simultaneously, differenttimes and combinations thereof.
 19. The method of claim 18, furthercomprising receiving feedback information data comprising at least oneselected from the group of: patient input data and sensed data; and,modifying the stimulation based on the input.
 20. The method of claim19, wherein the feedback information data relates to the autonomicnervous system response of the patient.